Differential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

J Pathol. 2021 Jan;253(1):55-67. doi: 10.1002/path.5548. Epub 2020 Oct 22.

Abstract

Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet- or drug-treated mice, in vitro primary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet- or CCl4 -treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin γ2. Both collagen I α1 and laminin γ2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl4 -mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: CCL20; NAFLD; NASH; SIRT1; SOCS; SREBP; STAT3; TM4SF5; laminin γ2; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Tetrachloride
  • Cell Line, Tumor
  • Chemical and Drug Induced Liver Injury / enzymology*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / pathology
  • Diet, High-Fat
  • Disease Progression
  • Extracellular Matrix / enzymology*
  • Extracellular Matrix / pathology
  • Humans
  • Lipid Metabolism*
  • Liver / enzymology*
  • Liver / pathology
  • Liver Cirrhosis, Experimental / chemically induced
  • Liver Cirrhosis, Experimental / enzymology*
  • Liver Cirrhosis, Experimental / genetics
  • Liver Cirrhosis, Experimental / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / chemically induced
  • Non-alcoholic Fatty Liver Disease / enzymology*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / pathology
  • Signal Transduction
  • Sirtuin 1 / metabolism*

Substances

  • Membrane Proteins
  • TM4SF5 protein, human
  • TM4SF5 protein, mouse
  • Carbon Tetrachloride
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1