FAM3C activates HSF1 to suppress hepatic gluconeogenesis and attenuate hyperglycemia of type 1 diabetic mice

// Zhenzhen Chen 1, 2, * , Junpei Wang 2, * , Weili Yang 2 , Ji Chen 2 , Yuhong Meng 2 , Biaoqi Feng 2 , Yujing Chi 3 , Bin Geng 1 , Yong Zhou 4 , Qinghua Cui 2, 5 and Jichun Yang 2 1 Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 100037, China 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of The Ministry of Education Center for Non-Coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China 3 Institute of Clinical Molecular Biology & Central Laboratory, Peking University People's Hospital, Beijing 100044, China 4 Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China 5 Department of Biomedical Informatics, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of The Ministry of Education, Center for Non-Coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China * These authors have contributed equally to this work Correspondence to: Jichun Yang, email: yangj@bjmu.edu.cn Keywords: FAM3C; hepatokine; HSF1; type 1 diabetes; gluconeogenesis Received: July 06, 2017 Accepted: October 30, 2017 Published: November 20, 2017 ABSTRACT FAM3C, a member of FAM3 gene family, has been shown to improve insulin resistance and hyperglycemia in obese mice. This study further determined whether FAM3C functions as a hepatokine to suppress hepatic gluconeogenesis of type 1 diabetic mice. In STZ-induced type 1 diabetic mouse liver, the FAM3C-HSF1-CaM signaling axis was repressed. Hepatic FAM3C overexpression activated HSF1-CaM-Akt pathway to repress gluconeogenic gene expression and ameliorate hyperglycemia of type 1 diabetic mice. Moreover, hepatic HSF1 overexpression also activated CaM-Akt pathway to repress gluconeogenic gene expression and improve hyperglycemia of type 1 diabetic mice. Hepatic FAM3C and HSF1 overexpression had little effect on serum insulin levels in type 1 diabetic mice. In cultured hepatocytes, conditioned medium of Ad-FAM3C-infected cells induced Akt phosphorylation. Moreover, Akt activation and gluconeogenesis repression induced by FAM3C overexpression were reversed by the treatment with anti-FAM3C antibodies. Treatment with recombinant FAM3C protein induced Akt activation in a HSF1- and CaM-dependent manner in cultured hepatocytes. Furthermore, recombinant FAM3C protein repressed gluconeogenic gene expression and gluconeogenesis by inactivating FOXO1 in a HSF1-dependent manner in cultured hepatocytes. In conclusion, FAM3C is a new hepatokine that suppresses hepatic gluconeogenic gene expression and gluconeogenesis independent of insulin by activating HSF1-CaM-Akt pathway.