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, China.
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, China.
Diabetes. 2017 May;66(5):1185-1197. doi: 10.2337/db16-0993. Epub 2017 Feb 28.
FAM3C is a member of the 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 protein kinase B (Akt) 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- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of FOXO1 and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated the CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, the 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 the management of type 2 diabetes and fatty liver.
FAM3C 是家族与序列相似性 3（FAM3）基因家族的成员，本研究旨在确定其在调节肝脏葡萄糖/脂质代谢中的作用和机制。在肥胖型糖尿病小鼠中，肝脏中 FAM3C 的表达减少，而肝脏中 FAM3C 的恢复改善了胰岛素抵抗、高血糖和脂肪肝。FAM3C 的过表达增加了热休克因子 1（HSF1）、钙调蛋白（CaM）和磷酸化蛋白激酶 B（Akt）的表达，并减少了糖尿病小鼠肝脏中糖异生和脂质生成基因的表达，抑制了糖异生和脂质沉积。在培养的肝细胞中，FAM3C 的过表达上调了 HSF1 的表达，通过诱导 CALM1 转录来增加 CaM 蛋白水平，从而在 Ca2+和胰岛素非依赖性方式下激活 Akt。此外，FAM3C 的过表达以 CaM 依赖的方式促进 FOXO1 的核输出，并抑制肝细胞中糖异生基因的表达和糖异生。肝 HSF1 的过表达激活了 CaM-Akt 通路，抑制了糖异生和脂质生成基因的表达，改善了肥胖型糖尿病小鼠的高血糖和脂肪肝。总之，FAM3C-HSF1-CaM-Akt 通路在独立于胰岛素和钙的情况下在肝细胞中调节葡萄糖和脂质代谢中发挥重要作用。恢复肝脏 FAM3C 的表达有利于 2 型糖尿病和脂肪肝的管理。
