Chen Zhenzhen, Wang Junpei, Yang Weili, Chen Ji, Meng Yuhong, Feng Biaoqi, Chi Yujing, Geng Bin, Zhou Yong, Cui Qinghua, Yang Jichun
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.
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.
Oncotarget. 2017 Nov 20;8(62):106038-106049. doi: 10.18632/oncotarget.22524. eCollection 2017 Dec 1.
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.
FAM3C是FAM3基因家族的成员之一，已被证明可改善肥胖小鼠的胰岛素抵抗和高血糖症。本研究进一步确定FAM3C是否作为一种肝源性激素发挥作用，以抑制1型糖尿病小鼠的肝脏糖异生。在链脲佐菌素诱导的1型糖尿病小鼠肝脏中，FAM3C - HSF1 - CaM信号轴受到抑制。肝脏FAM3C过表达激活HSF1 - CaM - Akt通路，从而抑制糖异生基因表达并改善1型糖尿病小鼠的高血糖症。此外，肝脏HSF1过表达也激活CaM - Akt通路，以抑制糖异生基因表达并改善1型糖尿病小鼠的高血糖症。肝脏FAM3C和HSF1过表达对1型糖尿病小鼠的血清胰岛素水平影响不大。在培养的肝细胞中，Ad - FAM3C感染细胞的条件培养基可诱导Akt磷酸化。此外，用抗FAM3C抗体处理可逆转FAM3C过表达诱导的Akt激活和糖异生抑制。在培养的肝细胞中，用重组FAM3C蛋白处理以HSF1和CaM依赖的方式诱导Akt激活。此外，重组FAM3C蛋白通过在培养的肝细胞中以HSF1依赖的方式使FOXO1失活，从而抑制糖异生基因表达和糖异生。总之，FAM3C是一种新的肝源性激素，通过激活HSF1 - CaM - Akt通路，独立于胰岛素抑制肝脏糖异生基因表达和糖异生。
