These authors contributed equally to this work.
Steatohepatitis/Metabolic Liver Disease
FAM3A activates PI3K p110α/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis
Article first published online: 27 MAR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 5, pages 1779–1790, May 2014
How to Cite
Wang, C., Chi, Y., Li, J., Miao, Y., Li, S., Su, W., Jia, S., Chen, Z., Du, S., Zhang, X., Zhou, Y., Wu, W., Zhu, M., Wang, Z., Yang, H., Xu, G., Wang, S., Yang, J. and Guan, Y. (2014), FAM3A activates PI3K p110α/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis. Hepatology, 59: 1779–1790. doi: 10.1002/hep.26945
Potential conflict of interest: Nothing to report.
Supported by grants from the Ministry of Science and Technology (2012CB517504/2009CB941603/2010CB912503) and the Natural Science Foundation (81170791/2011ZX09102/81322011). Support for this project was also provided by the “111 Project” of China and a grant from Beijing Natural Science Foundation (7122107).
- Issue published online: 23 APR 2014
- Article first published online: 27 MAR 2014
- Accepted manuscript online: 23 NOV 2013 03:28AM EST
- Manuscript Accepted: 18 NOV 2013
- Manuscript Received: 29 MAY 2013
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 p110α 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). (Hepatology 2014;59:1779–1790)