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

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.

• Authors: Jihye Ryu, Eunmi Kim, Min-Kyung Kang, Dae-Geun Song, Eun-Ae Shin, Haesong Lee, Jae Woo Jung, Seo Hee Nam, Ji Eon Kim, Hye-Jin Kim, Taekwon Son, Semi Kim, Hwi Young Kim, Jung Weon Lee
• Journal: The Journal of pathology (J Pathol) Vol. 253 Issue 1 Pg. 55-67 (01 2021) ISSN: 1096-9896 [Electronic] England
• PMID: 32918742 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

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

Topics

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