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Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation
  1. Samar H Ibrahim1,2,
  2. Petra Hirsova3,4,
  3. Gregory J Gores2
  1. 1 Division of Pediatrics Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
  2. 2 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
  3. 3 Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
  4. 4 Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
  1. Correspondence to Dr Gregory J Gores, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA; gores.gregory{at}mayo.edu

Abstract

A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed non-alcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.

  • inflammation
  • nonalcoholic steatohepatitis

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Footnotes

  • Contributors All authors have contributed equally in the outline of the review, research and writing of the manuscript. PH and SHI prepared the figures.

  • Funding This work was supported by NIH grants DK41876 (to GJG) and DK111397 (to SHI), North American Society of Pediatric Gastroenterology Hepatology and Nutrition Young Investigator Award/Nestle Nutrition Award and Gilead Sciences (to SHI), MH CZ–DRO (UHHK, 00179906) and the Mayo Clinic.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The author’s corresponding address and the third affiliation has been corrected.

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