Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

被引:37
作者
Batista, Thiago M. [1 ]
Dagdeviren, Sezin [2 ]
Carroll, Shannon H. [2 ]
Cai, Weikang [1 ]
Melnik, Veronika Y. [2 ]
Noh, Hye Lim [3 ]
Saengnipanthkul, Suchaorn [3 ]
Kim, Jason K. [3 ,4 ]
Kahn, C. Ronald [1 ]
Lee, Richard T. [2 ]
机构
[1] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA
[2] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[3] Univ Massachusetts, Med Sch, Program Mol Med, Worcester, MA 01655 USA
[4] Univ Massachusetts, Med Sch, Dept Med, Div Endocrinol Metab & Diabet, Worcester, MA 01655 USA
关键词
Arrdc3; alpha arrestins; liver; glucose metabolism; insulin action; PROTEIN-KINASE SGK; CANCER PROGRESSION; GENE-EXPRESSION; DISTINCT; ALPHA; FOXO1; FKHR; SENSITIVITY; RESISTANCE; LIGASE;
D O I
10.1073/pnas.1922370117
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the alpha-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of Arrdc3 (L-Arrdc3 KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, Arrdc3 is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.
引用
收藏
页码:6733 / 6740
页数:8
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