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
Affiliations
Yangie Dwi Pinanga
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Han Ah Lee
Department of Internal Medicine, Ewha Womans University College of Medicine, Division of Gastroenterology and Hepatology, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea
Eun-Ae Shin
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Haesong Lee
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Kyung-hee Pyo
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Ji Eon Kim
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Eun Hae Lee
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Wonsik Kim
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Soyeon Kim
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Hwi Young Kim
Department of Internal Medicine, Ewha Womans University College of Medicine, Division of Gastroenterology and Hepatology, Ewha Womans University Mokdong Hospital, Seoul 07985, Republic of Korea; Corresponding author
Jung Weon Lee
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Corresponding author
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.
