Knockdown of ACOT4 alleviates gluconeogenesis and lipid accumulation in hepatocytes
Qianqian Yuan,
Xiaomin Zhang,
Xiaonan Yang,
Qing Zhang,
Xiang Wei,
Zhimin Ding,
Jiajie Chen,
Hongting Hua,
Dake Huang,
Yongxia Xu,
Xiuyun Wang,
Chaobing Gao,
Shengxiu Liu,
Huabing Zhang
Affiliations
Qianqian Yuan
Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
Xiaomin Zhang
Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
Xiaonan Yang
Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
Qing Zhang
Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
Xiang Wei
Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China; Department of Hyperbaric Oxygen, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, China
Zhimin Ding
Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
Jiajie Chen
Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
Hongting Hua
Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
Dake Huang
Synthetic Laboratory of School of Basic Medicine Sciences, Anhui Medical University, Hefei, 230032, China
Yongxia Xu
Department of Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
Xiuyun Wang
Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China
Chaobing Gao
Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; Corresponding author.
Shengxiu Liu
Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; Corresponding author.
Huabing Zhang
Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China; Anhui Provincial Institute of Translational Medicine, Hefei, 230022, Anhui, China; Corresponding author. Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China.
Acyl-CoA thioesterase 4 (ACOT4) has been reported to be related to acetyl-CoA carboxylase activity regulation; However, its exact functions in liver lipid and glucose metabolism are still unclear. Here, we discovered explored the regulatory roles of ACOT4 in hepatic lipid and glucose metabolism in vitro. We found that the expression level of ACOT4 was significantly increased in the hepatic of db/db and ob/ob mice as well as obese mice fed a high fat diet. Adenovirus-mediated overexpression of ACOT4 promoted gluconeogenesis and high-glucose/high-insulin-induced lipid accumulation and impaired insulin sensitivity in primary mouse hepatocytes, whereas ACOT4 knockdown notably suppressed gluconeogenesis and decreased the triglycerides accumulation in hepatocytes. Furthermore, ACOT4 knockdown increased insulin-induced phosphorylation of AKT and GSK-3β in primary mouse hepatocytes. Mechanistically, we found that upregulation of ACOT4 expression inhibited AMP-activated protein kinase (AMPK) activity, and its knockdown had the opposite effect. However, activator A769662 and inhibitor compound C of AMPK suppressed the impact of the change in ACOT4 expression on AMPK activity. Our data indicated that ACOT4 is related to hepatic glucose and lipid metabolism, primarily via the regulation of AMPK activity. In conclusion, ACOT4 is a potential target for the therapy of non-alcoholic fatty liver (NAFLD) and type 2 diabetes.
