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Editorial| Volume 68, ISSUE 4, P643-645, April 2018

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Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications

  • Juliane I. Beier
    Correspondence
    Corresponding authors. Addresses: Department of Pharmacology & Toxicology, University of Louisville, 505 S. Hancock St, Louisville, KY 40292, USA. Tel.: +1 502 852 5157; fax: +1 502 852 3422 (J.I. Beier), or Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, Paseo del Dr. Begiristain s/n, E-20014 San Sebastian, Spain. Tel.: +34 943006067 (J. Banales).
    Affiliations
    Department of Pharmacology and Toxicology, Hepatobiology and Toxicology Program, University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
    Search for articles by this author
  • Jesus M. Banales
    Correspondence
    Corresponding authors. Addresses: Department of Pharmacology & Toxicology, University of Louisville, 505 S. Hancock St, Louisville, KY 40292, USA. Tel.: +1 502 852 5157; fax: +1 502 852 3422 (J.I. Beier), or Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, Paseo del Dr. Begiristain s/n, E-20014 San Sebastian, Spain. Tel.: +34 943006067 (J. Banales).
    Affiliations
    Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital – University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
    Search for articles by this author
Published:February 02, 2018DOI:https://doi.org/10.1016/j.jhep.2018.01.017
      Non-alcoholic fatty liver disease (NAFLD) represents a major health problem worldwide because of its high and rising prevalence, its association with cardiovascular disease, and its link with an increased risk of developing cirrhosis and hepatocellular carcinoma (HCC). NAFLD is classified into different degrees, from simple steatosis (overall 20–30% prevalence), which is considered “benign”, to steatohepatitis (NASH: 2–5% prevalence) and fibrosis.
      • Loomba R.
      • Sanyal A.J.
      The global NAFLD epidemic.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.
      The major risk factors of NAFLD include metabolic syndrome (i.e. obesity, diabetes, hypercholesterolemia and hypertriglyceridemia), sedentary lifestyle, genetic predispositions (e.g. PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738) and environmental factors (e.g. Western diet).
      • Loomba R.
      • Sanyal A.J.
      The global NAFLD epidemic.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.
      • Krawczyk M.
      • Jimenez-Aguero R.
      • Alustiza J.M.
      • Emparanza J.I.
      • Perugorria M.J.
      • Bujanda L.
      • et al.
      PNPLA3 p. I148M variant is associated with greater reduction of liver fat content after bariatric surgery.
      Indeed, the prevalence of NAFLD/NASH in patients with obesity and/or diabetes increases dramatically.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes.
      The differential diagnosis of NAFLD and NASH is currently available with accurate non-invasive methods based on serum metabolomics and/or imaging approaches,
      • Barr J.
      • Vazquez-Chantada M.
      • Alonso C.
      • Perez-Cormenzana M.
      • Mayo R.
      • Galan A.
      • et al.
      Liquid chromatography-mass spectrometry-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of nonalcoholic fatty liver disease.
      • Gallego-Duran R.
      • Cerro-Salido P.
      • Gomez-Gonzalez E.
      • Pareja M.J.
      • Ampuero J.
      • Rico M.C.
      • et al.
      Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease.
      and the determination and monitoring of liver fat concentration is also possible by magnetic resonance imaging.
      • Jimenez-Aguero R.
      • Emparanza J.I.
      • Beguiristain A.
      • Bujanda L.
      • Alustiza J.M.
      • Garcia E.
      • et al.
      Novel equation to determine the hepatic triglyceride concentration in humans by MRI: diagnosis and monitoring of NAFLD in obese patients before and after bariatric surgery.
      However, the precise determination of hepatocyte ballooning, inflammation and fibrosis still requires histological characterization by liver biopsy. The EASL–EASD–EASO clinical practice guidelines
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      recommend a Mediterranean diet and weight loss (7–10%) to obese patients, which have been shown to significantly improve the NAFLD activity score (NAS score).
      • Romero-Gomez M.
      • Zelber-Sagi S.
      • Trenell M.
      Treatment of NAFLD with diet, physical activity and exercise.
      However, since lifestyle modifications are often not completely successful, current research is aimed at unravelling the molecular mechanisms that trigger the development and progression of NAFLD. Such advances will aid the ultimate goal of providing new potential targets for pharmacological therapy, as well as discovering biomarkers for prognosis and response to therapy.

      Keywords

      Linked Article

      • Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice
        Journal of HepatologyVol. 68Issue 4
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          Non-alcoholic fatty liver disease (NAFLD) represents a multi-step biological disorder in the liver, increasing the risk of cirrhosis and tumorigenesis.1,2 The key aspects of steatohepatitis have been precisely mimicked by extensive basic and translation research. This has enabled the reductionist assessment of genes and dietary factors involved in the pathogenesis of NAFLD.3,4 Toxic lipid accumulation in the liver acts as the primary insult which initiates and propagates damage, leading to hepatocyte injury and resultant inflammation.
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