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Hepatic lipidomic remodeling in severe obesity manifests with steatosis and does not evolve with non-alcoholic steatohepatitis

Published:April 19, 2021DOI:https://doi.org/10.1016/j.jhep.2021.04.013

      Highlights

      • Distinct changes occur in the liver lipidome with non-alcoholic fatty liver disease (NAFLD).
      • There are few differences in the liver lipidome between simple steatosis and non-alcoholic steatohepatitis.
      • Excess body fat (subcutaneous and visceral adipose tissue) of obesity does not appear to affect the lipid profile of the liver or plasma.
      • Some liver lipids show a strong correlation with plasma lipids.
      • Lipidomics has the potential to be utilised as a non-invasive biomarker of NAFLD.

      Backgrounds & Aims

      Obesity often leads to non-alcoholic fatty liver disease (NAFLD), which can progress from simple steatosis (non-alcoholic fatty liver (NAFL)) to non-alcoholic steatohepatitis (NASH). The accumulation of certain lipid subtypes is linked with worsening metabolic and liver disease, however, specific changes during progression from No-NAFL to NAFL then NASH are unresolved. Herein, we characterise the liver, adipose tissue and plasma lipidome of worsening NAFLD in obesity, and evaluate the utility of plasma lipids as biomarkers of NAFLD.

      Methods

      Venous blood, liver, visceral and subcutaneous adipose tissue samples were obtained from 181 patients undergoing bariatric surgery. NAFLD severity was assessed histologically. Lipidomic analysis was performed using liquid chromatography-tandem mass spectrometry.

      Results

      The liver lipidome showed substantial changes with increasing steatosis, with increased triacylglycerols, diacylglycerols and sphingolipids including ceramide, dihydroceramide, hexosyl-ceramide and GM3 ganglioside species. These lipid species were also increased in plasma with increasing hepatic steatosis and showed strong correlations with liver lipids. Adipose tissue lipidomes showed no correlation with NAFLD. There were no significant changes in liver lipids with NASH compared to NAFL. The addition of plasma lipid variables to routine markers yielded significant improvements in diagnostic accuracy for NASH (AUROC 0.667 vs. 0.785, p = 0.025).

      Conclusion

      Overall, these data provide a detailed description of the lipidomic changes with worsening NAFLD, showing significant changes with steatosis but no additional changes with NASH. Alterations in the liver lipidome are paralleled by similar changes in plasma. Further investigation is warranted into the potential utility of plasma lipids as non-invasive biomarkers of NAFLD in obesity.

      Lay summary

      Non-alcoholic fatty liver disease (NAFLD) is characterised by distinct changes in the liver lipidome with steatosis. The development of non-alcoholic steatohepatitis (NASH) does not result in further changes in the lipidome. Lipids within body fat do not appear to influence the lipid profile of the liver or blood. Changes in liver lipids are paralleled by changes in blood lipids. This has potential to be developed into a non-invasive biomarker for NAFLD.

      Clinical trial number

      ACTRN12615000875505.

      Graphical abstract

      Keywords

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      References

        • Clark J.M.
        The epidemiology of nonalcoholic fatty liver disease in adults.
        J Clin Gastroenterol. 2006; 40: S5-S10
        • Coccia F.
        • Testa M.
        • Guarisco G.
        • Cristofano C.D.
        • Silecchia G.
        • Leonetti F.
        • et al.
        Insulin resistance, but not insulin response, during oral glucose tolerance test is associated to worse histological outcome in obese NAFLD.
        Nutr Metab Cardiovasc Dis. 2020; 30: 106-113
        • Bedossa P.
        • Tordjman J.
        • Aron-Wisnewsky J.
        • Poitou C.
        • Oppert J.-M.
        • Torcivia A.
        • et al.
        Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity.
        Gut. 2017; 66: 1688-1696
        • Lassailly G.
        • Caiazzo R.
        • Buob D.
        • Pigeyre M.
        • Verkindt H.
        • Labreuche J.
        • et al.
        Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.
        Gastroenterology. 2015; 149: 379-388
        • Younossi Z.
        Long-term outcomes of nonalcoholic fatty liver disease: from nonalcoholic steatohepatitis to nonalcoholic steatofibrosis.
        Clin Gastroenterol Hepatol. 2017; 15: 1141-1147
        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • Fazel Y.
        • Henry L.
        • Wymer M.
        Global epidemiology of nonalcoholic fatty liver disease - meta-analytic assessment of prevalence, incidence and outcomes.
        Hepatology. 2016; 64: 73-84
        • Donnelly K.L.
        • Smith C.I.
        • Schwarzenberg S.J.
        • Jessurun J.
        • Boldt M.D.
        • Parks E.J.
        Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
        J Clin Invest. 2005; 115: 1343-1351
        • Williams K.H.
        • Shackel N.A.
        • Gorrell M.D.
        • McLennan S.V.
        • Twigg S.M.
        Diabetes and nonalcoholic fatty liver disease: a pathogenic duo.
        Endocr Rev. 2013; 34: 84-129
        • Neuschwander-Tetri B.A.
        Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
        Hepatology. 2010; 52: 774-788
        • Unger R.H.
        Lipotoxic diseases.
        Annu Rev Med. 2002; 53: 319-336
        • Puri P.
        • Baillie R.A.
        • Wiest M.M.
        • Mirshahi F.
        • Choudhury J.
        • Cheung O.
        • et al.
        A lipidomic analysis of nonalcoholic fatty liver disease.
        Hepatology. 2007; 46: 1081-1090
        • Gorden D.L.
        • Myers D.S.
        • Ivanova P.T.
        • Fahy E.
        • Maurya M.R.
        • Gupta S.
        • et al.
        Biomarkers of NAFLD progression: a lipidomics approach to an epidemic.
        J Lipid Res. 2015; 56: 722-736
        • Luukkonen P.K.
        • Zhou Y.
        • Sadevirta S.
        • Leivonen M.
        • Arola J.
        • Oresic M.
        • et al.
        Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease.
        J Hepatol. 2016; 64: 1167-1175
        • Yamada K.
        • Mizukoshi E.
        • Sunagozaka H.
        • Arai K.
        • Yamashita T.
        • Takeshita Y.
        • et al.
        Characteristics of hepatic fatty acid composition in patients with nonalcoholic steatohepatitis.
        Liver Int. 2014; 35: 582-590
        • Anjani K.
        • Lhomme M.
        • Sokolovska N.
        • Poitou C.
        • Aron-Wisnewsky J.
        • Bouillot J.L.
        • et al.
        Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity.
        J Hepatol. 2015; 62: 905-912
        • Chaurasia B.
        • Summers S.A.
        Ceramides-Lipotoxic induces metabolic disorders.
        Trends Endocrinol Metab. 2015; 26: 538-550
        • Van der Poorten D.
        • Milner K.-L.
        • Hui J.M.
        • Hodge A.
        • Trenell M.I.
        • Kench J.G.
        • et al.
        Visceral fat: a key mediator of steatohepatitis in metabolic liver disease.
        Hepatology. 2008; 48: 449-457
        • Koutsari C.
        • Jensen M.D.
        Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity.
        J Lipid Res. 2006; 47: 1643-1650
        • Xia J.Y.
        • Holland W.L.
        • Kusminski C.M.
        • Sun K.
        • Sharma A.X.
        • Pearson M.J.
        • et al.
        Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis.
        Cell Metab. 2015; 22: 266-278
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • Charlton M.
        • Cusi K.
        • Rinella M.
        • et al.
        The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the AASLD.
        Hepatology. 2018; 67: 328-357
        • Ooi G.J.
        • Mgaieth S.
        • Eslick G.D.
        • Burton P.R.
        • Kemp W.
        • Roberts S.K.
        • et al.
        Systematic review and meta-analysis: non-invasive detection of NAFLD-related fibrosis in the obese.
        Obes Rev. 2017; 19: 281-294
        • Prati D.
        • Taioli E.
        • Zanella A.
        • Torre E.D.
        • Butelli S.
        • Vecchio E.D.
        • et al.
        Updated definitions of healthy ranges for serum alanine aminotransferase levels.
        Ann Intern Med. 2002; 137: 1-10
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • Diehl A.M.
        • Brunt E.M.
        • Cusi K.
        • et al.
        The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the AGA, AASLD, and ACG.
        Gastroenterology. 2012; 142: 1592-1609
        • Schindelin J.
        • Arganda-Carreras I.
        • Frise E.
        • Kaynig V.
        • Longair M.
        • Pietzsch T.
        • et al.
        Fiji: an open-source platform for biological-image analysis.
        Nat Methods. 2012; 9: 676-682
        • Brunt E.M.
        • Kleiner D.E.
        • Wilson L.A.
        • Belt P.
        • Neuschwander-Tetri B.A.
        Nonalcoholic fatty liver disease activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings.
        Hepatology. 2011; 53: 810-820
        • EASL-EASD-EASO
        Clinical practice guidelines for the management of NAFLD.
        J Hepatol. 2016; 64: 1388-1402
        • Kleiner D.E.
        • Brunt E.M.
        • Natta M.V.
        • Behling C.
        • Contos M.J.
        • Cummings O.W.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Tonks K.T.
        • Coster A.C.F.
        • Christopher M.J.
        • Chaudhuri R.
        • Xu A.
        • Gagnon-Bartsch J.
        • et al.
        Skeletal muscle and plasma lipidomic signatures of insulin resistance and overweight/obesity in humans.
        Obesity. 2016; 24: 908-916
        • Weir J.
        • Wong G.
        • Barlow C.K.
        • Greeve M.A.
        • Kowalczyk A.
        • Almasy L.
        • et al.
        Plasma lipid profiling in a large population-based cohort.
        J Lipid Res. 2013; 54: 2898-2908
        • Tyanova S.
        • Temi T.
        • Sinitcyn P.
        • Carlson A.
        • Hein M.Y.
        • Geiger T.
        • et al.
        The Perseus computational platform for comprehensive analysis of (prote)omics data.
        Nat Methods. 2016; 13: 731-740
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Doumas M.
        • Imprialos K.
        • Stavropoulos K.
        • Athyros V.G.
        What does the future hold for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis?.
        Curr Vasc Pharmacol. 2019; 17: 425-428
        • Parker B.L.
        • Calkin A.C.
        • Seldin M.M.
        • Keating M.F.
        • Tarling E.J.
        • Yang P.
        • et al.
        An integrative systems genetic analysis of mammalian lipid metabolism.
        Nature. 2019; 567: 187-193
        • Bedogni G.
        • Bellentani S.
        • Miglioli L.
        The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population.
        BMC Gastroenterol. 2006; 6: 33
        • Kotronen A.
        • Peltonen M.
        • Hakkarainen A.
        • Sevastianova K.
        • Bergholm R.
        • Johansson L.
        • et al.
        Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors.
        Gastroenterology. 2009; 137: 865-872
        • Svegliati-Baroni G.
        • Pierantonelli I.
        • Torquato P.
        • Marinelli R.
        • Ferreri C.
        • Chatgilialoglu C.
        • et al.
        Lipidomic biomarkers and mechanisms of lipotoxicity in non-alcoholic fatty liver disease.
        Free Radic Biol Med. 2019; 144: 293-309
        • Han M.S.
        • Park S.Y.
        • Shinzawa K.
        • Kim S.B.
        • Chung K.W.
        • Lee J.-H.
        • et al.
        Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes.
        J Lipid Res. 2008; 49: 84-97
        • Tan M.
        • Hao F.
        • Xu X.
        • Chisolm G.M.
        • Cui M.Z.
        Lysophosphatidylcholine activates a novel PKD2-mediated signaling pathway that controls monocyte migration.
        Arterioscler Thromb Vasc Biol. 2009; 29: 1376-1382
        • Jenkins B.
        • West J.A.
        • Koulman A.
        A review of odd-chain fatty acid metabolism and the role of pentadecanoic acid (c15:0) and heptadecanoic acid (c17:0) in health and disease.
        Molecules. 2015; 20: 2425-2444
        • Green C.R.
        • Wallace M.
        • Divakaruni A.S.
        • Phillips S.A.
        • Murphy A.N.
        • Ciaraldi T.P.
        • et al.
        Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis.
        Nat Chem Biol. 2016; 12: 15-21
        • Raichur S.
        • Wang S.T.
        • Chan P.W.
        • Li Y.
        • Ching J.
        • Chaurasia B.
        • et al.
        CerS2 haploinsufficiency inhibits oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance.
        Cell Metab. 2014; 20: 687-695
        • Turpin S.M.
        • Nicholls H.T.
        • Willmes D.M.
        • Mourier A.
        • Brodesser S.
        • Wunderlich C.M.
        • et al.
        Obesity-induced CerS60 dependent C16:0 ceramide production promotes weight gain and glucose intolerance.
        Cell Metab. 2014; 20: 678-686
        • Kurek K.
        • Piotrowska D.M.
        • Wiesiolek-Kurek P.
        • Lukaszuk B.
        • Chabowski A.
        • Gorski J.
        • et al.
        Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease.
        Liver Int. 2013; 34: 1074-1083
        • Apostolopoulou M.
        • Gordillo R.
        • Koliaki C.
        • Gancheva S.
        • Jelenik T.
        • DeFilippo E.
        • et al.
        Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis.
        Diabetes Care. 2018; 41: 1235-1243
        • Glass C.K.
        • Olefsky J.M.
        Inflammation and lipid signaling in the etiology of insulin resistance.
        Cell Metab. 2012; 15: 635-645
        • Boon J.
        • Hoy A.J.
        • Stark R.
        • Brown R.D.
        • Meex R.C.
        • Henstridge D.C.
        • et al.
        Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance.
        Diabetes. 2013; 62: 401-410
        • Test I.D.
        CERAM-MI-Heart ceramide, plasma.
        Mayo Clinic Laboratories, 2020