iScience (Sep 2023)

TM4SF5-mediated abnormal food-intake behavior and apelin expression facilitate non-alcoholic fatty liver disease features

  • Yangie Dwi Pinanga,
  • Han Ah Lee,
  • Eun-Ae Shin,
  • Haesong Lee,
  • Kyung-hee Pyo,
  • Ji Eon Kim,
  • Eun Hae Lee,
  • Wonsik Kim,
  • Soyeon Kim,
  • Hwi Young Kim,
  • Jung Weon Lee

Journal volume & issue
Vol. 26, no. 9
p. 107625

Abstract

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Summary: Transmembrane 4 L six family member 5 (TM4SF5) engages in non-alcoholic steatohepatitis (NASH), although its mechanistic roles are unclear. Genetically engineered Tm4sf5 mice fed ad libitum normal chow or high-fat diet for either an entire day or a daytime-feeding (DF) pattern were analyzed for metabolic parameters. Compared to wild-type and Tm4sf5−/− knockout mice, hepatocyte-specific TM4SF5-overexpressing Alb-TGTm4sf5−Flag (TG) mice showed abnormal food-intake behavior during the mouse-inactive daytime, increased apelin expression, increased food intake, and higher levels of NASH features. DF or exogenous apelin injection of TG mice caused severe hepatic pathology. TM4SF5-mediated abnormal food intake was correlated with peroxisomal β-oxidation, mTOR activation, and autophagy inhibition, with triggering NASH phenotypes. Non-alcoholic fatty liver disease (NAFLD) patients’ samples revealed a correlation between serum apelin and NAFLD activity score. Altogether, these observations suggest that hepatic TM4SF5 may cause abnormal food-intake behaviors to trigger steatohepatitic features via the regulation of peroxisomal β-oxidation, mTOR, and autophagy.

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