MAD1 deficiency accelerates hepatocellular proliferation via suppressing TGF-β signaling
Jiangming Deng,
Jianhui Teng,
Ting Xiao,
Jie Wen,
Wen Meng
Affiliations
Jiangming Deng
National Clinical Research Center for Metabolic Diseases and the Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; The Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Departments of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
Jianhui Teng
National Clinical Research Center for Metabolic Diseases and the Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; The Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
Ting Xiao
The Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Department of Hepatology, Hunan Children's Hospital, Changsha, 410000, Hunan, China
Jie Wen
Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China; Corresponding author. Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
Wen Meng
National Clinical Research Center for Metabolic Diseases and the Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; The Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Departments of Oncology, the Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China; Corresponding author. The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
Numerous researches have reported on the regulatory network of liver regeneration induced by partial hepatectomy (PH). However, information on key molecules and/or signaling pathways regulating the termination stage of liver regeneration remains limited. In this study, we identify hepatic mitotic arrest deficient 1 (MAD1) as a crucial regulator of transforming growth factor β (TGF-β) in the hepatocyte to repress liver regeneration. MAD1 has a low expression level at the rapid proliferation phase but significantly increases at the termination phase of liver regeneration. We show that MAD1 deficiency accelerates hepatocyte proliferation and enhances mitochondrial biogenesis and respiratory. Mechanistically, MAD1 deficiency in hepatocytes enhances mitochondrial function and promotes hepatocyte proliferation by suppressing TGF-β signaling. Our study reveals MAD1 as a novel suppressor of hepatocyte proliferation, which may provide a new therapeutic target for the recovery of liver function after liver transplant and partial hepatectomy.
