title: FAM3A activates PI3K p110α/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis.
abstract: 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 Ca(2+) levels and attenuated FAM3A-mediated PI3K/Akt activation. Moreover, FAM3A-induced Akt activation was completely abolished by the inhibition of calmodulin (CaM).
  
  
  CONCLUSIONS
  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 Ca(2+) /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).
authors.affiliation: Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Chunjiong
authors.initials: C
authors.lastname: Wang
authors.forename: Yujing
authors.initials: Y
authors.lastname: Chi
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yifei
authors.initials: Y
authors.lastname: Miao
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.forename: Shi
authors.initials: S
authors.lastname: Jia
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Shengnan
authors.initials: S
authors.lastname: Du
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Wenhan
authors.initials: W
authors.lastname: Wu
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Huaqian
authors.initials: H
authors.lastname: Yang
authors.forename: Guoheng
authors.initials: G
authors.lastname: Xu
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Wang
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000209:etiology; D005943:Gluconeogenesis; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016207:Cytokines; C582880:FAM3A protein, human; C000588926:FAM3A protein, mouse; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt