FAM3A Activates PI3K p110α/Akt Signaling to Ameliorate Hepatic Gluconeogenesis and Lipogenesis
FAM3A Activates PI3K p110α/Akt Signaling to Ameliorate Hepatic Gluconeogenesis and Lipogenesis
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DOI：
10.1002/hep.26945
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发表时间：
2014-05-01
期刊：
影响因子：
13.5
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
--
作者：
Wang, Chunjiong;Chi, Yujing;Guan, Youfei
FAM 3A属于一个新的类精氨酸基因家族，其生理作用在很大程度上仍然未知。在我们的研究中，我们发现db/db和高脂饮食（HFD）诱导的糖尿病小鼠肝脏中FAM 3A表达显著降低。FAM 3A的肝脏过表达显著减弱了高血糖症、胰岛素抵抗和脂肪肝，增加了Akt（pAkt）信号传导，并抑制了这些小鼠肝脏中的脂肪生成和脂肪生成。相比之下，小干扰RNA（siRNA）介导的肝FAM 3A敲低导致C57 BL/6小鼠的高血糖症，伴随pAkt水平降低以及肝脏中脂肪生成和脂肪生成增加。体外研究表明，FAM 3A主要定位于线粒体中，在那里它增加培养的肝细胞中三磷酸腺苷（ATP）的产生和分泌。FAM 3A通过PI 3 K的p110催化亚基以非胰岛素依赖的方式激活Akt。阻断P2 ATP受体或下游磷脂酶C（PLC）和IP 3R以及去除培养基钙均显著降低了FAM 3A诱导的胞浆游离Ca 2+水平升高，并减弱了FAM 3A介导的PI 3 K/Akt激活。此外，FAM 3A诱导的Akt激活被钙调蛋白（CaM）的抑制完全消除。结论：FAM 3A在肝脏中的葡萄糖和脂质代谢的调节中起关键作用，其中它通过Ca 2 +/CaM依赖性机制激活PI 3 K-Akt信号通路。上调肝脏FAM 3A的表达可能是治疗胰岛素抵抗、2型糖尿病和非酒精性脂肪性肝病（NAFLD）的一种有吸引力的手段。
FAM3A belongs to a novel cytokine-like gene family, and its physiological role remains largely unknown. In our study, we found a marked reduction of FAM3A expression in the livers of db/db and high-fat diet (HFD)-induced diabetic mice. Hepatic overexpression of FAM3A markedly attenuated hyperglycemia, insulin resistance, and fatty liver with increased Akt (pAkt) signaling and repressed gluconeogenesis and lipogenesis in the livers of those mice. In contrast, small interfering RNA (siRNA)-mediated knockdown of hepatic FAM3A resulted in hyperglycemia with reduced pAkt levels and increased gluconeogenesis and lipogenesis in the livers of C57BL/6 mice. In vitro study revealed that FAM3A was mainly localized in the mitochondria, where it increases adenosine triphosphate (ATP) production and secretion in cultured hepatocytes. FAM3A activated Akt through the p110 catalytic subunit of PI3K in an insulin-independent manner. Blockade of P2 ATP receptors or downstream phospholipase C (PLC) and IP3R and removal of medium calcium all significantly reduced FAM3A-induced increase in cytosolic free Ca2+ levels and attenuated FAM3A-mediated PI3K/Akt activation. Moreover, FAM3A-induced Akt activation was completely abolished by the inhibition of calmodulin (CaM). Conclusion: FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PI3K-Akt signaling pathway by way of a Ca2+/CaM-dependent mechanism. Up-regulating hepatic FAM3A expression may represent an attractive means for the treatment of insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD).