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Hepatokines and adipokines in NASH-related hepatocellular carcinoma

  • Ozlem Kucukoglu
    Affiliations
    Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
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  • Jan-Peter Sowa
    Affiliations
    Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
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  • Guillermo Daniel Mazzolini
    Affiliations
    Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina

    Liver Unit, Hospital Universitario Austral, Universidad Austral, Argentina
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  • Wing-Kin Syn
    Affiliations
    Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA

    Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA

    Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, 48940 Leioa, Vizcaya, Spain
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  • Ali Canbay
    Correspondence
    Corresponding author. Address: Director of the Department of Internal Medicine, Ruhr University Bochum, In der Schornau 23-25, 44892 Bochum, Germany. Tel.: +49 234 299-3401, fax: +49 234 299-3409.
    Affiliations
    Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany

    Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
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Open AccessPublished:November 05, 2020DOI:https://doi.org/10.1016/j.jhep.2020.10.030

      Summary

      The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors – in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin – for detection or even as therapeutic targets in NAFLD-related HCC.

      Keywords

      Introduction

      Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide, and the most common primary liver cancer.
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      Figure thumbnail gr1
      Fig. 1Associations of obesity and risk factors for NAFLD and NASH-related-HCC with hepatokines and adipokines.
      (A) Overview of generally known risk factors for NAFLD and NAFLD-related HCC and natural history of NAFLD. Obesity constitutes a risk factor for development of NAFLD, IR, hyperlipidaemia, and hypertension. These are components of the MetS, with NAFLD the hepatic manifestation. NAFLD ranges from simple hepatic steatosis (NAFL) to NASH, which is characterised by the presence of inflammation and hepatocyte ballooning with or without fibrosis. While NAFL is a risk for IR, NASH also constitutes a risk factor for progression from IR to T2DM and vice versa. NASH also increases the risk of hyperlipidaemia and hypertension. Approximately 60% of NAFLD cases are NAFL, while NASH occurs in 25–40%. Of patients with NASH, 25–35% develop simple to mild fibrosis. Cirrhosis and cirrhotic HCC are found in 9–20% of patients with NASH. Approximately 0.5% of the patients with NAFLD and 2.8% of the patients with NASH develop HCC.
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      Red arrows indicate a risk for the target condition; black arrows indicate a possible development/progression of the target condition. (B) Known regulations of hepatokines and adipokines during obesity and different stages of NAFLD. Black up-arrow: upregulated in condition; Black down-arrow: downregulated in condition; red arrow: (increased) hepatokine or adipokine facilitates or increases risk of developing target condition; green arrow: (increased) hepatokine or adipokine blocks or reduces risk of developing target condition. ANGPTL, angiopoietin-like protein; FGF, fibroblast growth factor; HCC, hepatocellular carcinoma; IR, insulin resistance; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; RBP4, retinol-binding protein 4; T2DM, type 2 diabetes mellitus.
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      Overall, the mechanisms of HCC development in NAFLD remain uncertain and merit in-depth investigation at the molecular level. In this context, hepatokines and adipokines have been gaining much attention in recent years. Herein, we will review the current understanding of how hepatokines and adipokines affect the pathogenesis of NASH-related HCC.
      NAFLD is the most common cause of chronic liver disease worldwide. The prevalence of NASH, the severe variant of NAFLD, is rising in parallel with the epidemics of obesity and type 2 diabetes mellitus.

      Risk factors and the pathogenesis of NASH and NASH-related HCC

      Obesity results from excess calorie uptake due to an unhealthy diet (i.e. high calorie diet) and a sedentary lifestyle, combined with the complex interplay between genes and the environment.
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      Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
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      Do hepatokines and adipokines influence NASH-related HCC?

      Liver and adipose tissue release organ-specific cytokines, termed hepatokines and adipokines, with autocrine, paracrine, and endocrine functions. Both hepatokines and adipokines have potent effects on metabolic homeostasis
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      Herein, we aim to provide an overview of the current knowledge on hepatokines (Table 1) and adipokines (Table 2) relevant to NAFLD, and discuss known associations with NASH-related HCC.
      HCC is a leading cause of cancer-related death in the general population, and it is estimated that the occurrence of NASH-related HCC will increase continually following the still ongoing increase of NAFLD prevalence.
      Table 1Overview of secreted proteins usually described as hepatokines.
      FactorKnown effectsSite(s) of expressionTarget site(s)References
      ANGPTL1
      • In vitro Inhibition of the HGF receptor
      • In vitro suppression of motility and metastasis of hepatoma cells
      • Serum concentrations inversely correlated to clinical outcome in HCC
      Vascularised tissueVascular endothelial cells
      • Carbone C.
      • Piro G.
      • Merz V.
      • Simionato F.
      • Santoro R.
      • Zecchetto C.
      • et al.
      Angiopoietin-like proteins in angiogenesis, inflammation and cancer.
      ,
      • Chen H.-A.
      • Kuo T.-C.
      • Tseng C.-F.
      • Ma J.-T.
      • Yang S.-T.
      • Yen C.-J.
      • et al.
      Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma.
      ANGPTL2
      • Increased expression in HCC and positive correlation with intrahepatic metastasis in HCC
      HepatocytesEndothelial cells
      • Carbone C.
      • Piro G.
      • Merz V.
      • Simionato F.
      • Santoro R.
      • Zecchetto C.
      • et al.
      Angiopoietin-like proteins in angiogenesis, inflammation and cancer.
      ,
      • Gao L.
      • Ge C.
      • Fang T.
      • Zhao F.
      • Chen T.
      • Yao M.
      • et al.
      ANGPTL2 promotes tumor metastasis in hepatocellular carcinoma.
      ANGPTL3
      • Decreased serum concentrations during fasting in obesity
      • Inhibits lipoprotein lipase
      HepatocytesAdipocytes
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ,
      • Cinkajzlová A.
      • Mráz M.
      • Lacinová Z.
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      • Kaválková P.
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      • et al.
      Angiopoietin-like protein 3 and 4 in obesity, type 2 diabetes mellitus, and malnutrition: the effect of weight reduction and realimentation.
      ANGPTL4
      • Increased serum concentrations during fasting in obesity
      • Low expression in HCC liver tissue compared to non-tumourous tissue
      • Suppression of tumorigenesis and metastasis in murine HCC models
      Liver and adipose tissueMultiple target cell populations, i.e. vascular endothelial cells, adipocytes.
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      • Cinkajzlová A.
      • Mráz M.
      • Lacinová Z.
      • Kloučková J.
      • Kaválková P.
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      • et al.
      Angiopoietin-like protein 3 and 4 in obesity, type 2 diabetes mellitus, and malnutrition: the effect of weight reduction and realimentation.
      • Mandard S.
      • Zandbergen F.
      • van Straten E.
      • Wahli W.
      • Kuipers F.
      • Müller M.
      • et al.
      The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity.
      ,
      • Ng K.T.-P.
      • Xu A.
      • Cheng Q.
      • Guo D.Y.
      • Lim Z.X.-H.
      • Sun C.K.-W.
      • et al.
      Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma.
      ANGPTL6
      • Increased serum ANGPTL6 levels in T2DM and with intake of vitamin D in obesity
      • Preventing the development of obesity and IR
      Hepatocyte-derived circulating factorProbably multiple target cell types
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ,
      • Oike Y.
      • Akao M.
      • Yasunaga K.
      • Yamauchi T.
      • Morisada T.
      • Ito Y.
      • et al.
      Angiopoietin-related growth factor antagonizes obesity and insulin resistance.
      • Ebert T.
      • Bachmann A.
      • Lössner U.
      • Kratzsch J.
      • Blüher M.
      • Stumvoll M.
      • et al.
      Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis.
      • Daneshzad E.
      • Farsad-Naeimi A.
      • Heshmati J.
      • Mirzaei K.
      • Maghbooli Z.
      • Keshavarz S.-A.
      The association between dietary antioxidants and adipokines level among obese women.
      ANGPTL8
      • Increased serum levels associated with the presence of liver steatosis and increased plasma triglyceride levels
      • Decreased serum levels in the development of MetS
      • Increased serum levels in IR, in impaired glucose regulation and T2DM
      • Increased lipogenesis and proliferation in HCC by ANGPTL8
      • Increased expression in HCC liver tissue, correlation with tumour size
      Liver tissue and VATProbably multiple target cell types, including autocrine effects
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ,
      • Wang C.
      • Tong Y.
      • Wen Y.
      • Cai J.
      • Guo H.
      • Huang L.
      • et al.
      Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth.
      • von Loeffelholz C.
      • Pfeiffer A.F.H.
      • Lock J.F.
      • Lieske S.
      • Döcke S.
      • Murahovschi V.
      • et al.
      ANGPTL8 (betatrophin) is expressed in visceral adipose tissue and relates to human hepatic steatosis in two independent clinical collectives.
      • Xu J.
      • Lin Y.
      • Zhou H.
      • Zhao L.
      • Xiang G.
      The correlation between circulating betatrophin and insulin resistance in general population: a meta-analysis.
      • Yin Y.
      • Ding X.
      • Peng L.
      • Hou Y.
      • Ling Y.
      • Gu M.
      • et al.
      Increased serum ANGPTL8 concentrations in patients with prediabetes and type 2 diabetes.
      • Wang S.
      • Hong X.
      • Tu Z.
      • Yuan G.
      Angiopoietin-like protein 8: an attractive biomarker for the evaluation of subjects with insulin resistance and related disorders.
      ,
      • Wang H.
      • Lai Y.
      • Han C.
      • Liu A.
      • Fan C.
      • Wang H.
      • et al.
      The effects of serum ANGPTL8/betatrophin on the risk of developing the metabolic syndrome – a prospective study.
      Fetuin-A
      • Increased serum levels in obesity, T2DM, MetS, NAFLD
      • Correlation with liver fibrosis stage in NAFLD
      HepatocytesCarrier protein (i.e. for fatty acids); adipocytes, muscle cells
      • Stefan N.
      • Häring H.-U.
      The role of hepatokines in metabolism.
      ,
      • von Loeffelholz C.
      • Horn P.
      • Birkenfeld A.L.
      • Claus R.A.
      • Metzing B.U.
      • Döcke S.
      • et al.
      Fetuin A is a predictor of liver fat in preoperative patients with nonalcoholic fatty liver disease.
      • Huang Y.
      • Huang X.
      • Ding L.
      • Wang P.
      • Peng K.
      • Chen Y.
      • et al.
      Serum fetuin-A associated with fatty liver index, early indicator of nonalcoholic fatty liver disease: a strobe-compliant article.
      • Kahraman A.
      • Sowa J.-P.
      • Schlattjan M.
      • Sydor S.
      • Pronadl M.
      • Wree A.
      • et al.
      Fetuin-A mRNA expression is elevated in NASH compared with NAFL patients.
      ,
      • Iroz A.
      • Couty J.-P.
      • Postic C.
      Hepatokines: unlocking the multi-organ network in metabolic diseases.
      ,
      • Sato M.
      • Kamada Y.
      • Takeda Y.
      • Kida S.
      • Ohara Y.
      • Fujii H.
      • et al.
      Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects.
      Fetuin-B
      • Increased serum levels in liver steatosis and T2DM
      • Negative correlation with non-invasive markers of liver fibrosis in NAFLD
      HepatocytesCarrier protein; multiple target tissues (i.e. neurons, adipocytes, hepatocytes)
      • Zhou W.
      • Yang J.
      • Zhu J.
      • Wang Y.
      • Wu Y.
      • Xu L.
      • et al.
      Fetuin B aggravates liver X receptor-mediated hepatic steatosis through AMPK in HepG2 cells and mice.
      ,
      • Ebert T.
      • Linder N.
      • Schaudinn A.
      • Busse H.
      • Berger J.
      • Lichtinghagen R.
      • et al.
      Association of fetuin B with markers of liver fibrosis in nonalcoholic fatty liver disease.
      FGF1
      • Increased FGF1 levels in obesity
      Hepatic stellate cells, adipocytesAuto-and paracrine targeting of adipocytes; hepatic stellate cells, hepatocytes
      • Schumacher J.D.
      • Guo G.L.
      Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors.
      ,
      • Mejhert N.
      • Galitzky J.
      • Pettersson A.T.
      • Bambace C.
      • Blomqvist L.
      • Bouloumié A.
      • et al.
      Mapping of the fibroblast growth factors in human white adipose tissue.
      FGF2
      • Increased FGF2 levels in obesity
      • Increased serum FGF2 levels in liver cirrhosis and HCC
      Hepatic stellate cells, adipocytes, hepatocytesMultiple target cell types, i.e. hepatic stellate cells
      • Schumacher J.D.
      • Guo G.L.
      Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors.
      ,
      • Mejhert N.
      • Galitzky J.
      • Pettersson A.T.
      • Bambace C.
      • Blomqvist L.
      • Bouloumié A.
      • et al.
      Mapping of the fibroblast growth factors in human white adipose tissue.
      ,
      • Jin-no K.
      • Tanimizu M.
      • Hyodo I.
      • Kurimoto F.
      • Yamashita T.
      Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease.
      FGF19, FGFR4 and β-Klotho
      • Increased FGFR4-mediated signalling and reduced serum FGF19 in NAFLD
      • Modestly increased serum FGF19 and FGFR4 in NASH patients with advanced ballooning
      • Increased FGF19 levels in diabetic obese and NASH patients with T2DM remission and NAFLD improvement after sleeve gastrectomy
      • FGF19 analogue reduces liver fat content in NASH
      • FGFR4 polymorphisms in patients with cirrhosis and HCC
      • Increased hepatic FGF19/FGFR4 expressions and serum levels associated with poor outcome in HCC
      • Increased FGF19/FGFR4 expressions together with EpCam in the progression of fatty liver (NAFLD) to HCC
      • Increased serum β-Klotho proteins in HCC
      Ileum, Liver, adipocytes, possibly cholangiocytesMature hepatocytes
      • Kan M.
      • Wu X.
      • Wang F.
      • McKeehan W.L.
      Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase.
      • Bechmann L.P.
      • Kocabayoglu P.
      • Sowa J.-P.
      • Sydor S.
      • Best J.
      • Schlattjan M.
      • et al.
      Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.
      • Jiao N.
      • Baker S.S.
      • Chapa-Rodriguez A.
      • Liu W.
      • Nugent C.A.
      • Tsompana M.
      • et al.
      Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.
      • Li Y.
      • Zhang W.
      • Doughtie A.
      • Cui G.
      • Li X.
      • Pandit H.
      • et al.
      Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma.
      ,
      • Sheu M.-J.
      • Hsieh M.-J.
      • Chiang W.-L.
      • Yang S.-F.
      • Lee H.-L.
      • Lee L.-M.
      • et al.
      Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.
      • Hyeon J.
      • Ahn S.
      • Lee J.J.
      • Song D.H.
      • Park C.-K.
      Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma.
      • Miura S.
      • Mitsuhashi N.
      • Shimizu H.
      • Kimura F.
      • Yoshidome H.
      • Otsuka M.
      • et al.
      Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
      ,
      • Huang H.-H.
      • Lee W.-J.
      • Chen S.-C.
      • Chen T.-F.
      • Lee S.-D.
      • Chen C.-Y.
      Bile acid and fibroblast growth factor 19 regulation in obese diabetics, and non-alcoholic fatty liver disease after sleeve gastrectomy.
      ,
      • Zhou Z.
      • Chen H.
      • Ju H.
      • Sun M.
      Circulating retinol binding protein 4 levels in nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      FGF21
      • Increased serum FGF21 levels in obesity, NAFLD, MetS, and T2DM
      • Positive correlation between liver FGF21 expression and adiposity, fasting insulin, intrahepatic triglycerides, and negative correlation with HDL cholesterol and BMI
      • Possible independent risk factor for progression to NASH
      • Increased serum FGF21 levels in liver cirrhosis and HCC
      Liver, adipocytes, pancreasAdipocytes, hypothalamus
      • Zhang X.
      • Yeung D.C.Y.
      • Karpisek M.
      • Stejskal D.
      • Zhou Z.-G.
      • Liu F.
      • et al.
      Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
      • Li H.
      • Fang Q.
      • Gao F.
      • Fan J.
      • Zhou J.
      • Wang X.
      • et al.
      Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride.
      • Hong E.S.
      • Lim C.
      • Choi H.Y.
      • Lee Y.K.
      • Ku E.J.
      • Moon J.H.
      • et al.
      Plasma fibroblast growth factor 21 levels increase with ectopic fat accumulation and its receptor levels are decreased in the visceral fat of patients with type 2 diabetes.
      • Yang C.
      • Lu W.
      • Lin T.
      • You P.
      • Ye M.
      • Huang Y.
      • et al.
      Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.
      ,
      • Yang M.
      • Xu D.
      • Liu Y.
      • Guo X.
      • Li W.
      • Guo C.
      • et al.
      Combined serum biomarkers in non-invasive diagnosis of non-alcoholic steatohepatitis.
      Hepassocin

      (HPS)
      • Increased serum levels in NAFLD and correlation with NAS
      • Low hepassocin expression in HCC
      LiverT-cells
      • Yu H.-T.
      • Yu M.
      • Li C.-Y.
      • Zhan Y.-Q.
      • Xu W.-X.
      • Li Y.-H.
      • et al.
      Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma.
      ,
      • Abdelmoemen G.
      • Khodeir S.A.
      • Zaki A.N.
      • Kassab M.
      • Abou-Saif S.
      • Abd-Elsalam S.
      Overexpression of hepassocin in diabetic patients with nonalcoholic fatty liver disease may facilitate increased hepatic lipid accumulation.
      ,
      • Yan J.
      • Yu Y.
      • Wang N.
      • Chang Y.
      • Ying H.
      • Liu W.
      • et al.
      LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma.
      RBP4
      • Controversial results for serum RBP4 and expression levels in NAFLD
      • Increased liver RBP4 protein expression in fibrosis, high lobular inflammation and NAS in NASH
      • Increased serum RBP4 levels and expressions in adipocytes in obesity
      • Decreased serum and hepatic RBP4 levels in liver cirrhosis correlated with reduced hepatic glucose production
      Hepatocytes, adipocytesRetinol delivery to diverse peripheral tissues (i.e. retina)
      • Kashyap S.R.
      • Diab D.L.
      • Baker A.R.
      • Yerian L.
      • Bajaj H.
      • Gray-McGuire C.
      • et al.
      Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort.
      • Alkhouri N.
      • Lopez R.
      • Berk M.
      • Feldstein A.E.
      Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease.
      • Milner K.-L.
      • van der Poorten D.
      • Xu A.
      • Bugianesi E.
      • Kench J.G.
      • Lam K.S.L.
      • et al.
      Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease.
      • Liu Y.
      • Mu D.
      • Chen H.
      • Li D.
      • Song J.
      • Zhong Y.
      • et al.
      Retinol-binding protein 4 induces hepatic mitochondrial dysfunction and promotes hepatic steatosis.
      • Wang X.
      • Chen X.
      • Zhang H.
      • Pang J.
      • Lin J.
      • Xu X.
      • et al.
      Circulating retinol-binding protein 4 is associated with the development and regression of non-alcoholic fatty liver disease.
      • Seo J.A.
      • Kim N.H.
      • Park S.Y.
      • Kim H.Y.
      • Ryu O.H.
      • Lee K.W.
      • et al.
      Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease.
      • Petta S.
      • Tripodo C.
      • Grimaudo S.
      • Cabibi D.
      • Cammà C.
      • Di Cristina A.
      • et al.
      High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis.
      • Graham T.E.
      • Yang Q.
      • Blüher M.
      • Hammarstedt A.
      • Ciaraldi T.P.
      • Henry R.R.
      • et al.
      Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.
      • Yang Q.
      • Graham T.E.
      • Mody N.
      • Preitner F.
      • Peroni O.D.
      • Zabolotny J.M.
      • et al.
      Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
      ,
      • Terra X.
      • Auguet T.
      • Broch M.
      • Sabench F.
      • Hernández M.
      • Pastor R.M.
      • et al.
      Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women.
      ,
      • Yagmur E.
      • Weiskirchen R.
      • Gressner A.M.
      • Trautwein C.
      • Tacke F.
      Insulin resistance in liver cirrhosis is not associated with circulating retinol-binding protein 4.
      Known effects and target sites in metabolic diseases (obesity, IR, T2DM, MetS, NAFLD, NASH) and HCC. ANGPTL, angiopoietin-like protein; FGF, fibroblast growth factor; HCC, hepatocellular carcinoma; IR, insulin resistance; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NAS, NAFLD activity scores; RBP4, retinol-binding protein 4; T2DM, type 2 diabetes mellitus; VAT, visceral adipose tissue.
      Table 2Overview of secreted proteins usually described as adipokines.
      FactorKnown effectsSite(s) of expressionTarget site(s)References
      Adiponectin
      • Decreased serum HMW adiponectin levels in obesity, advanced NAFLD and NASH patients with advanced ballooning, IR, T2DM, cardiovascular disease and MetS
      • Decreased serum adiponectin levels in HCC
      • Negative correlation with tumour size in HCC and with higher risk of HCC
      • Increased adiponectin levels in cirrhotic hepatitis virus infected-HCC patients
      • Adiponectin serum concentrations are an independent predictor of overall survival in HCC patients
      AdipocytesHepatocytes, hepatic stellate cells, muscle cells, probably more target cell populations (i.e. brain)
      • Aleksandrova K.
      • Boeing H.
      • Nöthlings U.
      • Jenab M.
      • Fedirko V.
      • Kaaks R.
      • et al.
      Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer.
      ,
      • Bechmann L.P.
      • Kocabayoglu P.
      • Sowa J.-P.
      • Sydor S.
      • Best J.
      • Schlattjan M.
      • et al.
      Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.
      ,
      • Ryo M.
      • Nakamura T.
      • Kihara S.
      • Kumada M.
      • Shibazaki S.
      • Takahashi M.
      • et al.
      Adiponectin as a biomarker of the metabolic syndrome.
      • Nannipieri M.
      • Cecchetti F.
      • Anselmino M.
      • Mancini E.
      • Marchetti G.
      • Bonotti A.
      • et al.
      Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis.
      • Lesmana C.R.
      • Lesmana L.A.
      • Akbar N.
      • Gani R.A.
      • Simandjuntak W.
      • Oemardi M.
      • et al.
      Clinical picture, insulin resistance, and adipocytokines profiles of nonalcoholic steatohepatitis (NASH) patients in Indonesia.
      • Li S.
      • Shin H.J.
      • Ding E.L.
      • Dam RM van
      Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis.
      • Polyzos S.A.
      • Toulis K.A.
      • Goulis D.G.
      • Zavos C.
      • Kountouras J.
      Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      • Kälsch J.
      • Bechmann L.P.
      • Heider D.
      • Best J.
      • Manka P.
      • Kälsch H.
      • et al.
      Normal liver enzymes are correlated with severity of metabolic syndrome in a large population based cohort.
      • Canbay A.
      • Kälsch J.
      • Neumann U.
      • Rau M.
      • Hohenester S.
      • Baba H.A.
      • et al.
      Non-invasive assessment of NAFLD as systemic disease-A machine learning perspective.
      ,
      • Saxena N.K.
      • Fu P.P.
      • Nagalingam A.
      • Wang J.
      • Handy J.
      • Cohen C.
      • et al.
      Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma.
      • Sadik N.A.E.-H.
      • Ahmed A.
      • Ahmed S.
      The significance of serum levels of adiponectin, leptin, and hyaluronic acid in hepatocellular carcinoma of cirrhotic and noncirrhotic patients.
      • da Silva T.E.
      • Costa-Silva M.
      • Correa C.G.
      • Denardin G.
      • Alencar M.L.A.
      • Coelho M.S.P.H.
      • et al.
      Clinical significance of serum adiponectin and resistin levels in liver cirrhosis.
      • Shen J.
      • Yeh C.-C.
      • Wang Q.
      • Gurvich I.
      • Siegel A.B.
      • Santella R.M.
      Plasma adiponectin and hepatocellular carcinoma survival among patients without liver transplantation.
      • Siegel A.B.
      • Goyal A.
      • Salomao M.
      • Wang S.
      • Lee V.
      • Hsu C.
      • et al.
      Serum adiponectin is associated with worsened overall survival in a prospective cohort of hepatocellular carcinoma patients.
      Apelin
      • Increased serum apelin levels in obesity in NAFLD patients
      • Apelin contributes to the angiogenesis of liver tissue in NASH
      • Increased apelin expression in HCC and correlation with tumorigenicity in HCC
      • Apelin stimulates arteriogenesis in HCC
      • Increased apelin receptor expression in the presence of microvascular invasion, intrahepatic metastasis, and early recurrence independent of HCC aetiology
      AdipocytesHeart, liver, adipose tissue, gastrointestinal tract, brain, endothelium, osteoblasts
      • Ando W.
      • Yokomori H.
      • Otori K.
      • Oda M.
      The apelin receptor APJ in hematopoietic stem cells/progenitor cells in the early stage of non-alcoholic steatohepatitis.
      ,
      • Muto J.
      • Shirabe K.
      • Yoshizumi T.
      • Ikegami T.
      • Aishima S.
      • Ishigami K.
      • et al.
      The apelin-APJ system induces tumor arteriogenesis in hepatocellular carcinoma.
      ,
      • Montazerifar F.
      • Bakhshipour A.R.
      • Karajibani M.
      • Torki Z.
      • Dashipour A.R.
      Serum omentin-1, vaspin, and apelin levels and central obesity in patients with nonalcoholic fatty liver disease.
      ,
      • Ercin C.N.
      • Dogru T.
      • Tapan S.
      • Kara M.
      • Haymana C.
      • Karadurmus N.
      • et al.
      Plasma apelin levels in subjects with nonalcoholic fatty liver disease.
      ,
      • Lee T.
      • Park C.-K.
      • Ha S.Y.
      Prognostic role of apelin receptor expression in hepatocellular carcinoma treated with curative surgical resection.
      ,
      • Chen H.
      • Wong C.-C.
      • Liu D.
      • Go M.Y.Y.
      • Wu B.
      • Peng S.
      • et al.
      APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.
      Chemerin
      • Association between increased serum chemerin levels and NAS, and with the presence of hepatocyte ballooning and inflammatory activity
      • Decreased chemerin VAT expression in high NAS score and after weight loss and/or bariatric surgery
      • Correlation between low serum chemerin levels and hepatic dysfunction, increased mortality in patients with decompensated cirrhosis and ascites
      • Independent prognostic factor in HCC, but no correlation with recurrence or prognosis in HCC patients
      • Association between increased serum chemerin with a poor prognosis of HCC
      Adipocytes, hepatocytes
      • Kukla M.
      • Zwirska-Korczala K.
      • Hartleb M.
      • Waluga M.
      • Chwist A.
      • Kajor M.
      • et al.
      Serum chemerin and vaspin in non-alcoholic fatty liver disease.
      • Yilmaz Y.
      • Yonal O.
      • Kurt R.
      • Alahdab Y.O.
      • Eren F.
      • Ozdogan O.
      • et al.
      Serum levels of omentin, chemerin and adipsin in patients with biopsy-proven nonalcoholic fatty liver disease.
      • Kajor M.
      • Kukla M.
      • Waluga M.
      • Liszka Ł.
      • Dyaczyński M.
      • Kowalski G.
      • et al.
      Hepatic chemerin mRNA in morbidly obese patients with nonalcoholic fatty liver disease.
      • Bekaert M.
      • Ouwens D.M.
      • Hörbelt T.
      • Van de Velde F.
      • Fahlbusch P.
      • Herzfeld de Wiza D.
      • et al.
      Reduced expression of chemerin in visceral adipose tissue associates with hepatic steatosis in patients with obesity.
      ,
      • Haberl E.M.
      • Pohl R.
      • Rein-Fischboeck L.
      • Feder S.
      • Sinal C.J.
      • Buechler C.
      Chemerin in a mouse model of non-alcoholic steatohepatitis and hepatocarcinogenesis.
      • Krautbauer S.
      • Wanninger J.
      • Eisinger K.
      • Hader Y.
      • Beck M.
      • Kopp A.
      • et al.
      Chemerin is highly expressed in hepatocytes and is induced in non-alcoholic steatohepatitis liver.
      • Döcke S.
      • Lock J.F.
      • Birkenfeld A.L.
      • Hoppe S.
      • Lieske S.
      • Rieger A.
      • et al.
      Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease.
      • Lin W.
      • Chen Y.-L.
      • Jiang L.
      • Chen J.-K.
      Reduced expression of chemerin is associated with a poor prognosis and a lowed infiltration of both dendritic cells and natural killer cells in human hepatocellular carcinoma.
      • Imai K.
      • Takai K.
      • Hanai T.
      • Shiraki M.
      • Suzuki Y.
      • Hayashi H.
      • et al.
      Impact of serum chemerin levels on liver functional reserves and platelet counts in patients with hepatocellular carcinoma.
      • Horn P.
      • von Loeffelholz C.
      • Forkert F.
      • Stengel S.
      • Reuken P.
      • Aschenbach R.
      • et al.
      Low circulating chemerin levels correlate with hepatic dysfunction and increased mortality in decompensated liver cirrhosis.
      Leptin
      • Increased serum leptin levels in obesity, T2DM, NASH and NAFL, but no significant predictor of NASH vs. non-NASH
      • Increased serum leptin levels in cirrhosis independent of HCC
      • Increased serum leptin levels are a risk factor for recurrent phase I/II of HCC after curative treatment
      • Increased serum leptin levels in cirrhotic patients with or without HCC vs. controls
      • Increased serum levels associated with carcinogenesis in obesity
      Adipocytes, stomach mucosa, muscleMultiple target cell populations; Brain (hypothalamus)
      • Watanabe N.
      • Takai K.
      • Imai K.
      • Shimizu M.
      • Naiki T.
      • Nagaki M.
      • et al.
      Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment.
      ,
      • Polyzos S.A.
      • Aronis K.N.
      • Kountouras J.
      • Raptis D.D.
      • Vasiloglou M.F.
      • Mantzoros C.S.
      Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      • Toczylowski K.
      • Hirnle T.
      • Harasiuk D.
      • Zabielski P.
      • Lewczuk A.
      • Dmitruk I.
      • et al.
      Plasma concentration and expression of adipokines in epicardial and subcutaneous adipose tissue are associated with impaired left ventricular filling pattern.
      • Sharma D.
      • Wang J.
      • Fu P.P.
      • Sharma S.
      • Nagalingam A.
      • Mells J.
      • et al.
      Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis.
      • Wang Y.-Y.
      • Lin S.-Y.
      Leptin in relation to hepatocellular carcinoma in patients with liver cirrhosis.
      • Andrighetto L.V.
      • Poziomyck A.K.
      Serum leptin levens and hepatocellular carcinoma: review article.
      ,
      • Garofalo C.
      • Surmacz E.
      Leptin and cancer.
      Resistin
      • Increased serum resistin levels in morbidly obese patients and T2DM
      • Independent risk factor and marker to identify HCV-related cirrhosis vs. HCV-related HCC development
      Adipose tissueHepatocytes
      • Degawa-Yamauchi M.
      • Bovenkerk J.E.
      • Juliar B.E.
      • Watson W.
      • Kerr K.
      • Jones R.
      • et al.
      Serum resistin (FIZZ3) protein is increased in obese humans.
      ,
      • McTernan P.G.
      • Fisher F.M.
      • Valsamakis G.
      • Chetty R.
      • Harte A.
      • McTernan C.L.
      • et al.
      Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes.
      ,
      • Elsayed E.Y.
      • Mosalam N.A.
      • Mohamed N.R.
      Resistin and insulin resistance: a link between inflammation and hepatocarcinogenesis.
      Visfatin
      • Increased serum visfatin levels in NAFLD
      • Increased visfatin liver expression in morbidly obese patients with T2DM.
      • No correlation between liver visfatin expression, NAS score, and inflammatory stages in obese patients with NAFLD
      • Association between increased visfatin levels and poor prognosis, stage progression and tumour enlargement in HCC
      • Increased liver expression in liver fibrosis and cirrhosis
      • Increased serum visfatin levels in viral-HCC
      Adipocytes (VAT and epicardial adipose tissue)Myocytes, hepatocytes, adipocytes, possibly pancreatic β-cells
      • Akbal E.
      • Koçak E.
      • Taş A.
      • Yüksel E.
      • Köklü S.
      Visfatin levels in nonalcoholic fatty liver disease.
      ,
      • Amirkalali B.
      • Sohrabi M.R.
      • Esrafily A.
      • Jalali M.
      • Gholami A.
      • Hosseinzadeh P.
      • et al.
      Association between nicotinamide phosphoribosyltransferase and de novo lipogenesis in nonalcoholic fatty liver disease.
      ,
      • Kukla M.
      • Ciupińska-Kajor M.
      • Kajor M.
      • Wyleżoł M.
      • Żwirska-Korczala K.
      • Hartleb M.
      • et al.
      Liver visfatin expression in morbidly obese patients with nonalcoholic fatty liver disease undergoing bariatric surgery.
      ,
      • Wu Z.
      • Sun Y.
      • Huang Y.
      • Zhu S.
      • Feng Y.
      • Ye H.
      • et al.
      Genetic variant in visfatin gene promoter contributes to reduced risk of hepatocellular carcinoma in a Chinese population.
      • Sun Y.
      • Zhu S.
      • Wu Z.
      • Huang Y.
      • Liu C.
      • Tang S.
      • et al.
      Elevated serum visfatin levels are associated with poor prognosis of hepatocellular carcinoma.
      • Ninomiya S.
      • Shimizu M.
      • Imai K.
      • Takai K.
      • Shiraki M.
      • Hara T.
      • et al.
      Possible role of visfatin in hepatoma progression and the effects of branched-chain amino acids on visfatin-induced proliferation in human hepatoma cells.
      Known effects and target sites in metabolic diseases (obesity, IR, T2DM, MetS, NAFLD, NASH) and HCC. HCC, hepatocellular carcinoma; HMW, high molecular weight; IR, insulin resistance; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NAS, NAFLD activity scores; T2DM, type-2 diabetes mellitus; VAT, visceral adipose tissue.

      Hepatokines

      Angiopoietin-like proteins

      Angiopoietin-like proteins (ANGPTLs) are circulating hepatokines that act on angiogenesis, inflammation and carcinogenesis.
      • Carbone C.
      • Piro G.
      • Merz V.
      • Simionato F.
      • Santoro R.
      • Zecchetto C.
      • et al.
      Angiopoietin-like proteins in angiogenesis, inflammation and cancer.
      Specifically, ANGPTL3, -4, -6 and -8 affect lipoprotein metabolism and the regulation of plasma lipid levels – the latter by inhibiting extracellular lipases;
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ANGPTL1, -2 and -8 have diverse roles in HCC tumorigenesis. To date, the role of the ANGPTLs in NASH-related HCC remains to be elucidated.
      In obese patients, fasting was found to decrease serum ANGPTL3 but increase ANGPTL4 levels, and only ANGPTL3 was reduced after a very low calorie diet.
      • Cinkajzlová A.
      • Mráz M.
      • Lacinová Z.
      • Kloučková J.
      • Kaválková P.
      • Kratochvílová H.
      • et al.
      Angiopoietin-like protein 3 and 4 in obesity, type 2 diabetes mellitus, and malnutrition: the effect of weight reduction and realimentation.
      ANGPTL3 directly inhibits lipoprotein lipase (LPL).
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ANGPTL4 is mainly expressed in the liver and adipose tissues, contributes to inhibition of LPL, and regulates triglyceride metabolism.
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ,
      • Mandard S.
      • Zandbergen F.
      • van Straten E.
      • Wahli W.
      • Kuipers F.
      • Müller M.
      • et al.
      The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity.
      In humans, under physiological conditions such as fasting, cold exposure, and exercise, the fatty acid-activated peroxisome proliferator-activated receptors (PPARs) regulate ANGPTL4 expression.
      • Dijk W.
      • Kersten S.
      Regulation of lipid metabolism by angiopoietin-like proteins.
      ,
      • Mandard S.
      • Zandbergen F.
      • van Straten E.
      • Wahli W.
      • Kuipers F.
      • Müller M.
      • et al.
      The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity.
      ANGPTL6 (also known as angiopoietin-related growth factor, or AGF) is a hepatocyte-derived circulating factor that inhibits the development of obesity and IR.
      • Oike Y.
      • Akao M.
      • Yasunaga K.
      • Yamauchi T.
      • Morisada T.
      • Ito Y.
      • et al.
      Angiopoietin-related growth factor antagonizes obesity and insulin resistance.
      Serum levels of ANGPTL6 positively correlate with fasting glucose in T2DM,
      • Oike Y.
      • Akao M.
      • Yasunaga K.
      • Yamauchi T.
      • Morisada T.
      • Ito Y.
      • et al.
      Angiopoietin-related growth factor antagonizes obesity and insulin resistance.
      ,
      • Ebert T.
      • Bachmann A.
      • Lössner U.
      • Kratzsch J.
      • Blüher M.
      • Stumvoll M.
      • et al.
      Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis.
      and with the intake of vitamin D in obese individuals.
      • Daneshzad E.
      • Farsad-Naeimi A.
      • Heshmati J.
      • Mirzaei K.
      • Maghbooli Z.
      • Keshavarz S.-A.
      The association between dietary antioxidants and adipokines level among obese women.
      ANGPTL8/betatrophin (also known as HCC associated protein, TD26, or lipasin)
      • Dong X.-Y.
      • Pang X.-W.
      • Yu S.-T.
      • Su Y.-R.
      • Wang H.-C.
      • Yin Y.-H.
      • et al.
      Identification of genes differentially expressed in human hepatocellular carcinoma by a modified suppression subtractive hybridization method.
      ,
      • Wang C.
      • Tong Y.
      • Wen Y.
      • Cai J.
      • Guo H.
      • Huang L.
      • et al.
      Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth.
      is expressed primarily in liver and visceral adipose tissue (VAT), and is associated with liver steatosis and increased plasma triglyceride levels in humans.
      • Wang C.
      • Tong Y.
      • Wen Y.
      • Cai J.
      • Guo H.
      • Huang L.
      • et al.
      Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth.
      ,
      • von Loeffelholz C.
      • Pfeiffer A.F.H.
      • Lock J.F.
      • Lieske S.
      • Döcke S.
      • Murahovschi V.
      • et al.
      ANGPTL8 (betatrophin) is expressed in visceral adipose tissue and relates to human hepatic steatosis in two independent clinical collectives.
      Serum levels of ANGPTL8 are significantly increased in IR
      • Xu J.
      • Lin Y.
      • Zhou H.
      • Zhao L.
      • Xiang G.
      The correlation between circulating betatrophin and insulin resistance in general population: a meta-analysis.
      and T2DM.
      • Yin Y.
      • Ding X.
      • Peng L.
      • Hou Y.
      • Ling Y.
      • Gu M.
      • et al.
      Increased serum ANGPTL8 concentrations in patients with prediabetes and type 2 diabetes.
      ,
      • Wang S.
      • Hong X.
      • Tu Z.
      • Yuan G.
      Angiopoietin-like protein 8: an attractive biomarker for the evaluation of subjects with insulin resistance and related disorders.
      ANGPTL8 requires ANGPTL3 to act on LPL, while ANGPTL8 alone has no demonstrable effect on LPL.
      • Kovrov O.
      • Kristensen K.K.
      • Larsson E.
      • Ploug M.
      • Olivecrona G.
      On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity.
      When brown adipose tissue (BAT) is exposed to the cold, overexpression of ANGPTL8 (and decreased ANGPTL4) upregulates LPL activity and triglyceride uptake.
      • Kovrov O.
      • Kristensen K.K.
      • Larsson E.
      • Ploug M.
      • Olivecrona G.
      On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity.
      ,
      • Fu Z.
      • Yao F.
      • Abou-Samra A.B.
      • Zhang R.
      Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family.
      A significant correlation between decreased serum ANGPTL8 levels and the development of MetS was also observed.
      • Wang H.
      • Lai Y.
      • Han C.
      • Liu A.
      • Fan C.
      • Wang H.
      • et al.
      The effects of serum ANGPTL8/betatrophin on the risk of developing the metabolic syndrome – a prospective study.
      Studies in human tissues and cell lines revealed diverging roles of different ANGPTLs in HCC. For example, ANGPTL1 suppressed Snail family of C2H2-type zinc finger transcription factor SNAI2 expression, which reduced cancer cell motility and metastasis and competed with hepatocyte growth factor for binding to the MET receptor in HCC cell lines; in addition, ANGPTL1 expression was inversely correlated with poor clinical outcomes in HCC.
      • Chen H.-A.
      • Kuo T.-C.
      • Tseng C.-F.
      • Ma J.-T.
      • Yang S.-T.
      • Yen C.-J.
      • et al.
      Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma.
      ANGPTL2 expression was higher in HCC tissues compared with matched non-cancerous liver tissues, and positively correlated with intrahepatic metastasis in patients with HCC.
      • Gao L.
      • Ge C.
      • Fang T.
      • Zhao F.
      • Chen T.
      • Yao M.
      • et al.
      ANGPTL2 promotes tumor metastasis in hepatocellular carcinoma.
      ANGPTL4 expression was lower in HCC tissue than non-tumorous liver tissue
      • Ng K.T.-P.
      • Xu A.
      • Cheng Q.
      • Guo D.Y.
      • Lim Z.X.-H.
      • Sun C.K.-W.
      • et al.
      Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma.
      and full-length ANGPTL4-overexpression in mice suppressed HCC tumorigenesis and metastasis.
      • Ng K.T.-P.
      • Xu A.
      • Cheng Q.
      • Guo D.Y.
      • Lim Z.X.-H.
      • Sun C.K.-W.
      • et al.
      Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma.
      ANGPTL8 was significantly overexpressed in HCC, and ANGPTL8 positively correlated with the tumour size in HCC.
      • Wang C.
      • Tong Y.
      • Wen Y.
      • Cai J.
      • Guo H.
      • Huang L.
      • et al.
      Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth.
      Lipogenesis and proliferation in HCC are also increased by ANGPTL8 through its interaction with nuclear sterol regulatory element-binding protein-1 (SREBP-1).
      • Wang C.
      • Tong Y.
      • Wen Y.
      • Cai J.
      • Guo H.
      • Huang L.
      • et al.
      Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth.
      Altogether, ANGPTL profiling in patients with NASH could identify patients at risk of HCC but further evaluation in larger studies is required.

      Fetuins A and B

      Fetuin-A (also known as α2-HS-glycoprotein) was the first hepatokine shown to be associated with metabolic disease. Serum levels are increased in obesity,
      • Stefan N.
      • Häring H.-U.
      The role of hepatokines in metabolism.
      ,
      • von Loeffelholz C.
      • Horn P.
      • Birkenfeld A.L.
      • Claus R.A.
      • Metzing B.U.
      • Döcke S.
      • et al.
      Fetuin A is a predictor of liver fat in preoperative patients with nonalcoholic fatty liver disease.
      and it is an early biomarker of NAFLD,
      • Huang Y.
      • Huang X.
      • Ding L.
      • Wang P.
      • Peng K.
      • Chen Y.
      • et al.
      Serum fetuin-A associated with fatty liver index, early indicator of nonalcoholic fatty liver disease: a strobe-compliant article.
      ,
      • Kahraman A.
      • Sowa J.-P.
      • Schlattjan M.
      • Sydor S.
      • Pronadl M.
      • Wree A.
      • et al.
      Fetuin-A mRNA expression is elevated in NASH compared with NAFL patients.
      MetS, IR
      • Peter A.
      • Kovarova M.
      • Staiger H.
      • Machann J.
      • Schick F.
      • Königsrainer A.
      • et al.
      The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans.
      and T2DM.
      • Iroz A.
      • Couty J.-P.
      • Postic C.
      Hepatokines: unlocking the multi-organ network in metabolic diseases.
      Fetuin-A was identified as an endogenous Toll-like receptor 4 (TLR4)-ligand in lipid-induced IR.
      • Pal D.
      • Dasgupta S.
      • Kundu R.
      • Maitra S.
      • Das G.
      • Mukhopadhyay S.
      • et al.
      Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.
      Secretion of fetuin-B by hepatocytes has also been described in liver steatosis and T2DM.
      • Meex R.C.
      • Hoy A.J.
      • Morris A.
      • Brown R.D.
      • Lo J.C.Y.
      • Burke M.
      • et al.
      Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism.
      ,
      • Meex R.C.R.
      • Watt M.J.
      Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance.
      Hepatic expression of both fetuins A and B increased in hepatic steatosis in humans.
      • Peter A.
      • Kovarova M.
      • Staiger H.
      • Machann J.
      • Schick F.
      • Königsrainer A.
      • et al.
      The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans.
      However, only weak correlations were observed between hepatic and serum concentrations of fetuins A and B.
      • Peter A.
      • Kovarova M.
      • Staiger H.
      • Machann J.
      • Schick F.
      • Königsrainer A.
      • et al.
      The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans.
      Human studies have meanwhile established that fetuin-A induces IR in concert with FFA via TLR4.
      • Meex R.C.R.
      • Watt M.J.
      Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance.
      ,
      • Peter A.
      • Kovarova M.
      • Staiger H.
      • Machann J.
      • Schick F.
      • Königsrainer A.
      • et al.
      The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans.
      ,
      • Lonardo A.
      • Lugari S.
      • Ballestri S.
      • Nascimbeni F.
      • Baldelli E.
      • Maurantonio M.
      A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?.
      Most data on fetuin-B derive from in vitro or animal studies which show that it may reduce insulin sensitivity but could actually cause glucose intolerance.
      • Lonardo A.
      • Lugari S.
      • Ballestri S.
      • Nascimbeni F.
      • Baldelli E.
      • Maurantonio M.
      A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?.
      ,
      • Best J.D.
      • Kahn S.E.
      • Ader M.
      • Watanabe R.M.
      • Ni T.C.
      • Bergman R.N.
      Role of glucose effectiveness in the determination of glucose tolerance.
      Treatment of HepG2 cells with recombinant fetuin-B increased hepatic lipid accumulation, while loss of fetuin-B inhibited hepatocellular lipid accumulation, improved glucose metabolism,
      • Meex R.C.
      • Hoy A.J.
      • Morris A.
      • Brown R.D.
      • Lo J.C.Y.
      • Burke M.
      • et al.
      Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism.
      ,
      • Šeda O.
      • Cahová M.
      • Míková I.
      • Šedová L.
      • Daňková H.
      • Heczková M.
      • et al.
      Hepatic gene expression profiles differentiate steatotic and non-steatotic grafts in liver transplant recipients.
      and reduced intrahepatic and serum triglyceride contents in mice.
      • Zhou W.
      • Yang J.
      • Zhu J.
      • Wang Y.
      • Wu Y.
      • Xu L.
      • et al.
      Fetuin B aggravates liver X receptor-mediated hepatic steatosis through AMPK in HepG2 cells and mice.
      Fetuin-B seems to reduce phosphorylation of 5'adenosine monophosphate-activated protein kinase (AMPK) and to inhibit LXR-SREBP1c-dependent lipogenesis, while increasing fatty acid oxidation in vitro and in vivo in mice.
      • Zhou W.
      • Yang J.
      • Zhu J.
      • Wang Y.
      • Wu Y.
      • Xu L.
      • et al.
      Fetuin B aggravates liver X receptor-mediated hepatic steatosis through AMPK in HepG2 cells and mice.
      In patients with NAFLD, serum levels of both fetuins A and B negatively correlated with liver fibrosis stage
      • Sato M.
      • Kamada Y.
      • Takeda Y.
      • Kida S.
      • Ohara Y.
      • Fujii H.
      • et al.
      Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects.
      and other markers of liver fibrosis.
      • Ebert T.
      • Linder N.
      • Schaudinn A.
      • Busse H.
      • Berger J.
      • Lichtinghagen R.
      • et al.
      Association of fetuin B with markers of liver fibrosis in nonalcoholic fatty liver disease.
      High serum fetuin-A concentrations were also detected in patients with HCC.
      • Aleksandrova K.
      • Boeing H.
      • Nöthlings U.
      • Jenab M.
      • Fedirko V.
      • Kaaks R.
      • et al.
      Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer.
      Taken together fetuin-A and B seem to negatively affect insulin sensitivity and glucose tolerance, suggesting a role in NAFLD and probably NAFLD-related HCC via IR.

      Fibroblast growth factors

      Fibroblast growth factors (FGFs) are secreted signalling proteins which regulate energy metabolism.
      • Nies V.J.M.
      • Sancar G.
      • Liu W.
      • van Zutphen T.
      • Struik D.
      • Yu R.T.
      • et al.
      Fibroblast growth factor signaling in metabolic regulation.
      Canonical FGF functions comprise control of cell proliferation, differentiation and survival.
      • Ornitz D.M.
      • Itoh N.
      The fibroblast growth factor signaling pathway.
      ,
      • Wilkie A.O.
      • Morriss-Kay G.M.
      • Jones E.Y.
      • Heath J.K.
      Functions of fibroblast growth factors and their receptors.
      The FGF family includes 7 subfamilies with 18 secreted FGFs, which interact with 4 tyrosine kinase FGF receptors (FGFRs) via different cofactors.
      • Schumacher J.D.
      • Guo G.L.
      Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors.
      FGFs bind heparin (mainly paracrine FGFs) – except for the FGF19 subfamily (FGF19, FGF21, and FGF23), which requires the Klotho proteins as cofactors (mainly endocrine FGFs).
      • Schumacher J.D.
      • Guo G.L.
      Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors.
      ,
      • Goetz R.
      • Beenken A.
      • Ibrahimi O.A.
      • Kalinina J.
      • Olsen S.K.
      • Eliseenkova A.V.
      • et al.
      Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.
      Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis
      • Wang J.-N.
      • Li L.
      • Li L.-Y.
      • Yan Q.
      • Li J.
      • Xu T.
      Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis.
      and are activated by neighbouring cells and secreted factors. FGFs produced by HSCs – i.e. FGF1, FGF2, FGF7, FGF15, FGF9 – bind FGFRs on hepatocytes.
      • Schumacher J.D.
      • Guo G.L.
      Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors.
      Some FGFs (FGF1, FGF2, FGF7, FGF19, FGF18 and FHF2 [previously known as FGF13]) are also expressed in subcutaneous white adipose tissue (scWAT).
      • Mejhert N.
      • Galitzky J.
      • Pettersson A.T.
      • Bambace C.
      • Blomqvist L.
      • Bouloumié A.
      • et al.
      Mapping of the fibroblast growth factors in human white adipose tissue.
      The particular functions of FGFs depend on the FGF/FGFRs and the expression of heparin/klotho proteins in target tissue.
      • Goetz R.
      • Beenken A.
      • Ibrahimi O.A.
      • Kalinina J.
      • Olsen S.K.
      • Eliseenkova A.V.
      • et al.
      Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.
      ,
      • Mejhert N.
      • Galitzky J.
      • Pettersson A.T.
      • Bambace C.
      • Blomqvist L.
      • Bouloumié A.
      • et al.
      Mapping of the fibroblast growth factors in human white adipose tissue.
      ,
      • Dailey L.
      • Ambrosetti D.
      • Mansukhani A.
      • Basilico C.
      Mechanisms underlying differential responses to FGF signaling.
      Here, we briefly discuss the most relevant FGFs relating to human metabolism and liver disease.
      FGF1 and FGF2 are involved in HSC activation.
      • Schumacher J.D.
      • Guo G.L.
      Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors.
      One study mapped the expression and secretion of FGFs in scWAT from non-obese and obese individuals.
      • Mejhert N.
      • Galitzky J.
      • Pettersson A.T.
      • Bambace C.
      • Blomqvist L.
      • Bouloumié A.
      • et al.
      Mapping of the fibroblast growth factors in human white adipose tissue.
      Apparently only FGF1 is produced in adipocytes and acts as an auto- and paracrine factor. Only the levels of FGF1 and FGF2 significantly differed between non-obese and obese female individuals. While FGF1 expression levels were doubled among obese individuals compared to non-obese controls, FGF2 expression in scWAT was significantly reduced.
      • Mejhert N.
      • Galitzky J.
      • Pettersson A.T.
      • Bambace C.
      • Blomqvist L.
      • Bouloumié A.
      • et al.
      Mapping of the fibroblast growth factors in human white adipose tissue.
      Serum FGF2 levels were also found to be increased in cirrhosis and HCC.
      • Jin-no K.
      • Tanimizu M.
      • Hyodo I.
      • Kurimoto F.
      • Yamashita T.
      Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease.
      In the liver and adipocytes, endocrine FGF19 and FGF21 activate FGFR4 and FGFR1c together with cofactor β-Klotho, which is abundantly expressed in hepatocytes. FGF19 and FGF21 control bile acid, lipid and glucose metabolism.
      • Luo Y.
      • Yang C.
      • Lu W.
      • Xie R.
      • Jin C.
      • Huang P.
      • et al.
      Metabolic regulator βKlotho interacts with fibroblast growth factor receptor 4 (FGFR4) to induce apoptosis and inhibit tumor cell proliferation.
      ,
      • Kurosu H.
      • Choi M.
      • Ogawa Y.
      • Dickson A.S.
      • Goetz R.
      • Eliseenkova A.V.
      • et al.
      Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.
      FGFR4 is predominantly expressed in mature hepatocytes.
      • Kan M.
      • Wu X.
      • Wang F.
      • McKeehan W.L.
      Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase.
      In a study in humans, serum FGF19 and FGFR4 levels paralleled those of serum bile acids and were significantly increased in patients with NASH and advanced ballooning.
      • Bechmann L.P.
      • Kocabayoglu P.
      • Sowa J.-P.
      • Sydor S.
      • Best J.
      • Schlattjan M.
      • et al.
      Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.
      In patients with NAFLD, serum concentrations of primary and secondary bile acids were increased as a result of impaired FXR and FGFR4-mediated signalling.
      • Jiao N.
      • Baker S.S.
      • Chapa-Rodriguez A.
      • Liu W.
      • Nugent C.A.
      • Tsompana M.
      • et al.
      Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.
      ,
      • Li Y.
      • Zhang W.
      • Doughtie A.
      • Cui G.
      • Li X.
      • Pandit H.
      • et al.
      Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma.
      Recently, a multicentre, randomized, double-blinded, placebo-controlled, phase II trial was performed to test the safety and efficacy of an FGF19 analogue for patients with NASH (NAFLD activity score [NAS] ≥4, fibrosis stage: 1–3; liver fat ≥8%). Twelve weeks of treatment led to a rapid and significant reduction in the amount of liver fat.
      • Harrison S.A.
      • Rinella M.E.
      • Abdelmalek M.F.
      • Trotter J.F.
      • Paredes A.H.
      • Arnold H.L.
      • et al.
      NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
      FGFR4 polymorphisms have also been detected in patients with cirrhosis and HCC
      • Sheu M.-J.
      • Hsieh M.-J.
      • Chiang W.-L.
      • Yang S.-F.
      • Lee H.-L.
      • Lee L.-M.
      • et al.
      Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.
      and the overexpression of hepatic and serum FGF19/FGFR4 has been associated with poor outcomes in patients with HCC.
      • Li Y.
      • Zhang W.
      • Doughtie A.
      • Cui G.
      • Li X.
      • Pandit H.
      • et al.
      Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma.
      ,
      • Hyeon J.
      • Ahn S.
      • Lee J.J.
      • Song D.H.
      • Park C.-K.
      Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma.
      ,
      • Miura S.
      • Mitsuhashi N.
      • Shimizu H.
      • Kimura F.
      • Yoshidome H.
      • Otsuka M.
      • et al.
      Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
      This was confirmed by our own group, demonstrating increased serum FGF19 in NASH, NASH-HCC and in particular cirrhotic NASH-HCC.
      • Sydor S.
      • Best J.
      • Messerschmidt I.
      • Manka P.
      • Vilchez-Vargas R.
      • Brodesser S.
      • et al.
      Altered microbiota diversity and bile acid signaling in cirrhotic and noncirrhotic NASH-HCC.
      FGF19 was also correlated with alterations in bile acids and tumour markers. The β-Klotho proteins are also increased in the serum and livers of patients with HCC as a result of ER stress.
      • Li Y.
      • Zhang W.
      • Doughtie A.
      • Cui G.
      • Li X.
      • Pandit H.
      • et al.
      Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma.
      ,
      • Miura S.
      • Mitsuhashi N.
      • Shimizu H.
      • Kimura F.
      • Yoshidome H.
      • Otsuka M.
      • et al.
      Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.
      While a significant number of individuals with NAFLD develops HCC without advanced liver fibrosis or cirrhosis, the underlying mechanisms remain poorly understood.
      The hepatokine FGF21 is a regulator of glucose and lipid homeostasis and a stress response hormone. FGF21 has a positive effect on hepatic steatosis, enhances lipid oxidation, suppresses de novo lipogenesis in the liver,
      • Coskun T.
      • Bina H.A.
      • Schneider M.A.
      • Dunbar J.D.
      • Hu C.C.
      • Chen Y.
      • et al.
      Fibroblast growth factor 21 corrects obesity in mice.
      and improves IR by inhibiting mTOR.
      • Xu J.
      • Lloyd D.J.
      • Hale C.
      • Stanislaus S.
      • Chen M.
      • Sivits G.
      • et al.
      Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice.
      Serum FGF21 levels are significantly increased in overweight/obese patients
      • Zhang X.
      • Yeung D.C.Y.
      • Karpisek M.
      • Stejskal D.
      • Zhou Z.-G.
      • Liu F.
      • et al.
      Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
      and in those with NAFLD,
      • Li H.
      • Fang Q.
      • Gao F.
      • Fan J.
      • Zhou J.
      • Wang X.
      • et al.
      Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride.
      MetS,
      • Zhang X.
      • Yeung D.C.Y.
      • Karpisek M.
      • Stejskal D.
      • Zhou Z.-G.
      • Liu F.
      • et al.
      Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
      T2DM
      • Hong E.S.
      • Lim C.
      • Choi H.Y.
      • Lee Y.K.
      • Ku E.J.
      • Moon J.H.
      • et al.
      Plasma fibroblast growth factor 21 levels increase with ectopic fat accumulation and its receptor levels are decreased in the visceral fat of patients with type 2 diabetes.
      as well as HCC and cirrhosis.
      • Yang C.
      • Lu W.
      • Lin T.
      • You P.
      • Ye M.
      • Huang Y.
      • et al.
      Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.
      Liver FGF21 expressions were positively correlated with adiposity, fasting insulin and intrahepatic triglycerides,
      • Zhang X.
      • Yeung D.C.Y.
      • Karpisek M.
      • Stejskal D.
      • Zhou Z.-G.
      • Liu F.
      • et al.
      Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
      ,
      • Li H.
      • Fang Q.
      • Gao F.
      • Fan J.
      • Zhou J.
      • Wang X.
      • et al.
      Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride.
      but negatively correlated with HDL cholesterol and BMI.
      • Zhang X.
      • Yeung D.C.Y.
      • Karpisek M.
      • Stejskal D.
      • Zhou Z.-G.
      • Liu F.
      • et al.
      Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
      Elevated serum FGF21 levels were also independently associated with an increased risk of developing MetS.
      • Zhang X.
      • Yeung D.C.Y.
      • Karpisek M.
      • Stejskal D.
      • Zhou Z.-G.
      • Liu F.
      • et al.
      Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.
      These results were consistent with a study in obese children with and without NAFLD. Serum FGF21 concentrations were significantly higher in obese children with NAFLD and were positively correlated with steatosis grades (severe vs. mild) in biopsies and with the total intrahepatic lipid content assessed by magnetic resonance proton spectroscopy.
      • Flisiak-Jackiewicz M.
      • Bobrus-Chociej A.
      • Wasilewska N.
      • Tarasow E.
      • Wojtkowska M.
      • Lebensztejn D.M.
      Can hepatokines be regarded as novel non-invasive serum biomarkers of intrahepatic lipid content in obese children?.
      Serum FGF21 levels positively correlated with NAS and pathological characteristics of NAFLD; patients with advanced NASH could be identified by FGF21 serum levels in combination with cytokeratin-18-M30 antigen, IL-1Ra, pigment epithelium-derived factor and osteoprotegerin.
      • Yang M.
      • Xu D.
      • Liu Y.
      • Guo X.
      • Li W.
      • Guo C.
      • et al.
      Combined serum biomarkers in non-invasive diagnosis of non-alcoholic steatohepatitis.
      Moreover, hepatic FGF21 protein expression is significantly induced in murine models of hepatocarcinogenesis and during hepatic stress in humans.
      • Yang C.
      • Lu W.
      • Lin T.
      • You P.
      • Ye M.
      • Huang Y.
      • et al.
      Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.
      Increased hepatic FGF21 expression has been observed in stage A HCC, NAFLD, cirrhosis and hepatitis C, so its applicability as a marker for a specific disease could be limited. Further studies on FGF21 and its association with hepatic injury beyond NAFLD and MetS are required.

      Hepassocin

      Hepassocin (HPS) (also known as hepatocyte-derived fibrinogen-related protein 1) is a hepatokine that is involved in liver regeneration and is induced by the hepatocyte nuclear factor 1α (HNF1α)-regulated IL-6/IL-6R/STAT3 pathway in hepatoma cells in vitro.
      • Yu H.-T.
      • Yu M.
      • Li C.-Y.
      • Zhan Y.-Q.
      • Xu W.-X.
      • Li Y.-H.
      • et al.
      Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma.
      High levels of serum HPS were detected in mice and patients with NAFLD, and levels of HPS correlated with NAS.
      • Abdelmoemen G.
      • Khodeir S.A.
      • Zaki A.N.
      • Kassab M.
      • Abou-Saif S.
      • Abd-Elsalam S.
      Overexpression of hepassocin in diabetic patients with nonalcoholic fatty liver disease may facilitate increased hepatic lipid accumulation.
      Serum HPS concentrations also correlated with those of inflammatory cytokines (e.g. IL-1b, IL-6, TNF-α) and the expression of lipogenesis-related markers (FASN, ACC, SREBP-1). Hepatic overexpression of HPS induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway in mice.
      • Wu H.-T.
      • Lu F.-H.
      • Ou H.-Y.
      • Su Y.-C.
      • Hung H.-C.
      • Wu J.-S.
      • et al.
      The role of hepassocin in the development of non-alcoholic fatty liver disease.
      Additionally, HPS has been shown to contribute to the development of IR and T2DM through ERK1/2 activation in HPS knock-out mice.
      • Demchev V.
      • Malana G.
      • Vangala D.
      • Stoll J.
      • Desai A.
      • Kang H.W.
      • et al.
      Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization.
      HPS expression in BAT and liver was increased following partial hepatectomy in mice
      • Demchev V.
      • Malana G.
      • Vangala D.
      • Stoll J.
      • Desai A.
      • Kang H.W.
      • et al.
      Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization.
      and by IL-6 in vitro,
      • Yu H.-T.
      • Yu M.
      • Li C.-Y.
      • Zhan Y.-Q.
      • Xu W.-X.
      • Li Y.-H.
      • et al.
      Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma.
      suggesting a cross talk between the injured liver and adipose tissue.
      • Demchev V.
      • Malana G.
      • Vangala D.
      • Stoll J.
      • Desai A.
      • Kang H.W.
      • et al.
      Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization.
      Oleic acid increased HPS expression by activating signal transducer and activator of transcription 3 (STAT3) signalling and inducing IR in HepG2 cells,
      • Cheng K.-P.
      • Ou H.-Y.
      • Hung H.-C.
      • Li C.-H.
      • Fan K.-C.
      • Wu J.-S.
      • et al.
      Unsaturated fatty acids increase the expression of hepassocin through a signal transducer and activator of transcription 3-dependent pathway in HepG2 cells.
      while palmitic acid induced HPS through p38-modulated binding of C/EBPβ to the HPS promoter in mice.
      • Jung T.W.
      • Chung Y.H.
      • Kim H.-C.
      • Abd El-Aty A.M.
      • Jeong J.H.
      Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle.
      HPS administration protected against liver injury and improved survival in rats with hepatitis.
      • Li C.-Y.
      • Cao C.-Z.
      • Xu W.-X.
      • Cao M.-M.
      • Yang F.
      • Dong L.
      • et al.
      Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure.
      In contrast, liver-specific HPS expression is repressed in HCC cells and patients with HCC,
      • Yu H.-T.
      • Yu M.
      • Li C.-Y.
      • Zhan Y.-Q.
      • Xu W.-X.
      • Li Y.-H.
      • et al.
      Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma.
      ,
      • Yan J.
      • Yu Y.
      • Wang N.
      • Chang Y.
      • Ying H.
      • Liu W.
      • et al.
      LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma.
      likely through a decrease in HNF1α expression.
      • Yu H.-T.
      • Yu M.
      • Li C.-Y.
      • Zhan Y.-Q.
      • Xu W.-X.
      • Li Y.-H.
      • et al.
      Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma.
      ,
      • Ni Q.
      • Ding K.
      • Wang K.-Q.
      • He J.
      • Yin C.
      • Shi J.
      • et al.
      Deletion of HNF1α in hepatocytes results in fatty liver-related hepatocellular carcinoma in mice.
      It remains to be elucidated if HPS has protective effects on metabolic alterations in the liver and adipocytes in NASH and NASH-related HCC.

      Retinol-binding protein 4

      Retinol-binding protein 4 (RBP4) is a specific retinol/vitamin A carrier protein belonging to the lipocalin family. This plasma protein is primarily synthesised in the liver but also released from adipose tissue as an adipokine.
      • Perduca M.
      • Nicolis S.
      • Mannucci B.
      • Galliano M.
      • Monaco H.L.
      Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein.
      All-trans-retinol binding induces RBP4 secretion, and vitamin A deficiency causes RBP4 accumulation in human liver.
      • Perduca M.
      • Nicolis S.
      • Mannucci B.
      • Galliano M.
      • Monaco H.L.
      Human plasma retinol-binding protein (RBP4) is also a fatty acid-binding protein.
      ,
      • Ronne H.
      • Ocklind C.
      • Wiman K.
      • Rask L.
      • Obrink B.
      • Peterson P.A.
      Ligand-dependent regulation of intracellular protein transport: effect of vitamin a on the secretion of the retinol-binding protein.
      In turn RBP4 is released upon saturation with retinol. In NAFLD, liver vitamin A homeostasis is disrupted, which may contribute to disease progression.
      • Zhong G.
      • Kirkwood J.
      • Won K.-J.
      • Tjota N.
      • Jeong H.
      • Isoherranen N.
      Characterization of vitamin A metabolome in human livers with and without nonalcoholic fatty liver disease.
      Though the role of RBP4 in NAFLD and IR is controversial, as has been reviewed elsewhere.
      • Kotnik P.
      • Fischer-Posovszky P.
      • Wabitsch M.
      RBP4: a controversial adipokine.
      Some studies found no correlation between liver and plasma RBP4 levels and NAFLD/NASH severity,
      • Kashyap S.R.
      • Diab D.L.
      • Baker A.R.
      • Yerian L.
      • Bajaj H.
      • Gray-McGuire C.
      • et al.
      Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort.
      • Alkhouri N.
      • Lopez R.
      • Berk M.
      • Feldstein A.E.
      Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease.
      • Milner K.-L.
      • van der Poorten D.
      • Xu A.
      • Bugianesi E.
      • Kench J.G.
      • Lam K.S.L.
      • et al.
      Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease.
      while others detected a correlation between circulating RBP4 levels and NAFLD development.
      • Liu Y.
      • Mu D.
      • Chen H.
      • Li D.
      • Song J.
      • Zhong Y.
      • et al.
      Retinol-binding protein 4 induces hepatic mitochondrial dysfunction and promotes hepatic steatosis.
      ,
      • Wang X.
      • Chen X.
      • Zhang H.
      • Pang J.
      • Lin J.
      • Xu X.
      • et al.
      Circulating retinol-binding protein 4 is associated with the development and regression of non-alcoholic fatty liver disease.
      In a large prospective study, baseline RBP4 was positively associated with the occurrence of NAFLD, and elevated levels of serum RBP4 were detected in patients with NAFLD.
      • Wang X.
      • Chen X.
      • Zhang H.
      • Pang J.
      • Lin J.
      • Xu X.
      • et al.
      Circulating retinol-binding protein 4 is associated with the development and regression of non-alcoholic fatty liver disease.
      ,
      • Seo J.A.
      • Kim N.H.
      • Park S.Y.
      • Kim H.Y.
      • Ryu O.H.
      • Lee K.W.
      • et al.
      Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease.
      In NASH, high hepatic RBP4 protein expression correlated with a moderate to severe fibrosis score (≥F2, with a high NAS score) and high lobular inflammation scores.
      • Petta S.
      • Tripodo C.
      • Grimaudo S.
      • Cabibi D.
      • Cammà C.
      • Di Cristina A.
      • et al.
      High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis.
      RBP4 expression by adipocytes may further contribute to IR and T2DM in obesity.
      • Graham T.E.
      • Yang Q.
      • Blüher M.
      • Hammarstedt A.
      • Ciaraldi T.P.
      • Henry R.R.
      • et al.
      Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.
      ,
      • Yang Q.
      • Graham T.E.
      • Mody N.
      • Preitner F.
      • Peroni O.D.
      • Zabolotny J.M.
      • et al.
      Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
      Both obese-non-diabetic and obese-diabetic patients had 1.9-fold elevated serum RBP4 levels compared to lean controls,
      • Graham T.E.
      • Yang Q.
      • Blüher M.
      • Hammarstedt A.
      • Ciaraldi T.P.
      • Henry R.R.
      • et al.
      Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.
      ,
      • Yang Q.
      • Graham T.E.
      • Mody N.
      • Preitner F.
      • Peroni O.D.
      • Zabolotny J.M.
      • et al.
      Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
      and serum levels of RBP4 positively correlated with BMI and IR.
      • Yang Q.
      • Graham T.E.
      • Mody N.
      • Preitner F.
      • Peroni O.D.
      • Zabolotny J.M.
      • et al.
      Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
      Conversely other reports showed serum and hepatic RBP4 levels to negatively correlate with liver fibrosis stage.
      • Alkhouri N.
      • Lopez R.
      • Berk M.
      • Feldstein A.E.
      Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease.
      While these results seem inconclusive, they could be explained by the pleiotropic functions of RBP4, the differences among NAFLD disease stages, and the characteristics of the different populations studied. In cirrhosis, RBP4 expression correlated with reduced hepatic glucose production,
      • Bahr M.J.
      • Boeker K.H.W.
      • Manns M.P.
      • Tietge U.J.F.
      Decreased hepatic RBP4 secretion is correlated with reduced hepatic glucose production but is not associated with insulin resistance in patients with liver cirrhosis.
      but not with IR.
      • Alkhouri N.
      • Lopez R.
      • Berk M.
      • Feldstein A.E.
      Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease.
      ,
      • Bahr M.J.
      • Boeker K.H.W.
      • Manns M.P.
      • Tietge U.J.F.
      Decreased hepatic RBP4 secretion is correlated with reduced hepatic glucose production but is not associated with insulin resistance in patients with liver cirrhosis.
      • Schina M.
      • Koskinas J.
      • Tiniakos D.
      • Hadziyannis E.
      • Savvas S.
      • Karamanos B.
      • et al.
      Circulating and liver tissue levels of retinol-binding protein-4 in non-alcoholic fatty liver disease.
      • Nobili V.
      • Alkhouri N.
      • Alisi A.
      • Ottino S.
      • Lopez R.
      • Manco M.
      • et al.
      Retinol-binding protein 4: a promising circulating marker of liver damage in pediatric nonalcoholic fatty liver disease.
      Impaired vitamin A homeostasis and deficiency may also be seen in liver fibrosis and cirrhosis.
      • Saeed A.
      • Dullaart R.P.F.
      • Schreuder T.C.M.A.
      • Blokzijl H.
      • Faber K.N.
      Disturbed vitamin A metabolism in non-alcoholic fatty liver disease (NAFLD).
      Collectively, the data suggests that RBP4 could be a marker to distinguish simple steatosis from NASH with advanced fibrosis/cirrhosis or NASH-related cirrhotic HCC. Further studies controlling for the separate impact of IR and fibrogenesis on RBP4 expression in the liver and adipose tissue are required.

      Adipokines

      Adiponectin

      Adiponectin is a key adipokine with important metabolic functions including glucose regulation, insulin sensitising, and fatty acid oxidation. Adiponectin also has anti-inflammatory, anti-fibrotic, and anti-tumourigenic activities
      • Valenti L.
      • Bugianesi E.
      • Pajvani U.
      • Targher G.
      Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes?.
      ,
      • Adolph T.E.
      • Grander C.
      • Grabherr F.
      • Tilg H.
      Adipokines and non-alcoholic fatty liver disease: multiple interactions.
      ,
      • Carbone F.
      • La Rocca C.
      • Matarese G.
      Immunological functions of leptin and adiponectin.
      ,
      • Wree A.
      • Kahraman A.
      • Gerken G.
      • Canbay A.
      Obesity affects the liver - the link between adipocytes and hepatocytes.
      and is an important mediator of FGF21 activity.
      • Holland W.L.
      • Adams A.C.
      • Brozinick J.T.
      • Bui H.H.
      • Miyauchi Y.
      • Kusminski C.M.
      • et al.
      An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice.
      Circulating levels of adiponectin negatively correlate with BMI and are decreased in patients with advanced NASH, IR, T2DM, and MetS.
      • Bechmann L.P.
      • Kocabayoglu P.
      • Sowa J.-P.
      • Sydor S.
      • Best J.
      • Schlattjan M.
      • et al.
      Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.
      ,
      • Ryo M.
      • Nakamura T.
      • Kihara S.
      • Kumada M.
      • Shibazaki S.
      • Takahashi M.
      • et al.
      Adiponectin as a biomarker of the metabolic syndrome.
      • Nannipieri M.
      • Cecchetti F.
      • Anselmino M.
      • Mancini E.
      • Marchetti G.
      • Bonotti A.
      • et al.
      Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis.
      • Lesmana C.R.
      • Lesmana L.A.
      • Akbar N.
      • Gani R.A.
      • Simandjuntak W.
      • Oemardi M.
      • et al.
      Clinical picture, insulin resistance, and adipocytokines profiles of nonalcoholic steatohepatitis (NASH) patients in Indonesia.
      • Li S.
      • Shin H.J.
      • Ding E.L.
      • Dam RM van
      Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis.
      • Polyzos S.A.
      • Toulis K.A.
      • Goulis D.G.
      • Zavos C.
      • Kountouras J.
      Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      • Kälsch J.
      • Bechmann L.P.
      • Heider D.
      • Best J.
      • Manka P.
      • Kälsch H.
      • et al.
      Normal liver enzymes are correlated with severity of metabolic syndrome in a large population based cohort.
      • Canbay A.
      • Kälsch J.
      • Neumann U.
      • Rau M.
      • Hohenester S.
      • Baba H.A.
      • et al.
      Non-invasive assessment of NAFLD as systemic disease-A machine learning perspective.
      High molecular weight (HMW) adiponectin, which is thought to be the most biologically active form, has been associated with IR, cardiovascular diseases, and liver fibrosis in humans.
      • Polyzos S.A.
      • Toulis K.A.
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