Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice.

Chen Z, Ding L, Yang W et al.

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.

Diabetes. Feb 2017.

FAM3C is a member of family with sequence similarity 3 (FAM3) gene family, and this study determined its role and mechanism in regulation of hepatic glucose/lipid metabolism. In obese diabetic mice, FAM3C expression was reduced in the liver, and hepatic FAM3C restoration improved insulin resistance, hyperglycemia and fatty liver. FAM3C overexpression increased the expression of heat shock factor 1 (HSF1), calmodulin (CaM) and phosphorylated Akt (pAkt), and reduced that of gluconeogenic and lipogenic genes in diabetic mouse livers with the suppression of gluconeogenesis and lipid deposition. In cultured hepatocytes, FAM3C overexpression upregulated HSF1 expression, which elevated CaM protein level by inducing CALM1 transcription to activate Akt in a Ca(2+)- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of forkhead box protein O1 (FOXO1), and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression, and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for management of type 2 diabetes and fatty liver.


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