A Positive Feedback Loop Between RIP3 and JNK Controls Non-Alcoholic Steatohepatitis

EMBO Mol Med. 2014 Aug;6(8):1062-74. doi: 10.15252/emmm.201403856.

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non-alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death-so far characterized as hepatocyte apoptosis-represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3-dependent "necroptosis" in NASH and NASH-induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase-8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun-(N)-terminal Kinase (JNK). Furthermore, RIP3-dependent JNK activation promotes the release of pro-inflammatory mediators like MCP-1, thereby attracting macrophages to the injured liver and further augmenting RIP3-dependent signaling, cell death, and liver fibrosis. Thus, RIP3-dependent necroptosis controls NASH-induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH.

Keywords: Caspase‐8; MCP‐1; biliary ductular reaction; liver fibrosis; necroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Humans
  • Liver / pathology
  • MAP Kinase Kinase 4 / metabolism*
  • Mice
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • MAP Kinase Kinase 4