Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene

被引:104
作者
Han, Yamei [1 ]
Hu, Zhimin [1 ]
Cui, Aoyuan [1 ]
Liu, Zhengshuai [1 ]
Ma, Fengguang [1 ]
Xue, Yaqian [1 ]
Liu, Yuxiao [1 ]
Zhang, Feifei [1 ]
Zhao, Zehua [2 ]
Yu, Yanyan [3 ]
Gao, Jing [1 ]
Wei, Chun [4 ]
Li, Jingya [3 ]
Fang, Jing [1 ]
Li, Jia [3 ]
Fan, Jian-Gao [2 ]
Song, Bao-Liang [5 ]
Li, Yu [1 ]
机构
[1] Chinese Acad Sci, CAS Key Lab Nutr Metab & Food Safety, Shanghai Inst Nutr & Hlth, Shanghai Inst Biol Sci,Univ Chinese Acad Sci, Shanghai 200031, Peoples R China
[2] Shanghai Jiao Tong Univ, Xinhua Hosp, Dept Gastroenterol, Sch Med, Shanghai 200092, Peoples R China
[3] Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Univ Chinese Acad Sci, Shanghai 201203, Peoples R China
[4] Zhejiang Univ Technol, Coll Biotechnol & Bioengn, Hangzhou 310014, Zhejiang, Peoples R China
[5] Wuhan Univ, Hubei Key Lab Cell Homeostasis, Coll Life Sci, Inst Adv Studies, Wuhan 430072, Peoples R China
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
ATTENUATE HEPATIC STEATOSIS; IMPROVES HYPERLIPIDEMIA; PROTEASOMAL DEGRADATION; CHOLESTEROL-SYNTHESIS; SREBP; INSIG-1; PROTEIN; HOMEOSTASIS; MICE; RESISTANCE;
D O I
10.1038/s41467-019-08585-4
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-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPK-dependent phosphorylation ablates Insig's interaction with E3 ubiquitin ligase gp78 and represses its ubiquitination and degradation, whereas AMPK deficiency shows opposite effects. Interestingly, activation of AMPK by metformin causes an augmentation of Insig stability and reduction of lipogenic gene expression, and leads to the attenuation of hepatic steatosis in HFHS diet-fed mice. Moreover, hepatic overexpression of Insig-1 rescues hepatic steatosis in liver-specific AMPK alpha 2 knockout mice fed with HFHS diet. These findings uncover a novel effector of AMPK. Targeting Insig may have the therapeutic potential for treating fatty liver disease and related disorders.
引用
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页数:13
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共 41 条
[1]   Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene [J].
Amemiya-Kudo, M ;
Shimano, H ;
Yoshikawa, T ;
Yahagi, N ;
Hasty, AH ;
Okazaki, H ;
Tamura, Y ;
Shionoiri, F ;
Iizuka, Y ;
Ohashi, K ;
Osuga, J ;
Harada, K ;
Gotoda, T ;
Sato, R ;
Kimura, S ;
Ishibashi, S ;
Yamada, N .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (40) :31078-31085
[2]   Liver adenosine monophosphate-activated kinase-α2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin [J].
Andreelli, F ;
Foretz, M ;
Knauf, C ;
Cani, PD ;
Perrin, C ;
Iglesias, MA ;
Pillot, B ;
Bado, A ;
Tronche, F ;
Mithieux, G ;
Vaulont, S ;
Burcelin, R ;
Viollet, B .
ENDOCRINOLOGY, 2006, 147 (05) :2432-2441
[3]   Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism [J].
Brown, AJ ;
Sun, LP ;
Feramisco, JD ;
Brown, MS ;
Goldstein, JL .
MOLECULAR CELL, 2002, 10 (02) :237-245
[4]   The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J].
Brown, MS ;
Goldstein, JL .
CELL, 1997, 89 (03) :331-340
[5]   Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans [J].
Brown, MS ;
Ye, J ;
Rawson, RB ;
Goldstein, JL .
CELL, 2000, 100 (04) :391-398
[6]   Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor α [J].
Chen, Xuqing ;
Zhang, Feifei ;
Gong, Qi ;
Cui, Aoyuan ;
Zhuo, Shu ;
Hu, Zhimin ;
Han, Yamei ;
Gao, Jing ;
Sun, Yixuan ;
Liu, Zhengshuai ;
Yang, Zhongnan ;
Le, Yingying ;
Gao, Xianfu ;
Dong, Lily Q. ;
Gao, Xin ;
Li, Yu .
DIABETES, 2016, 65 (07) :1904-1915
[7]   Schoenheimer effect explained - feedback regulation of cholesterol synthesis in mice mediated by Insig proteins [J].
Engelking, LJ ;
Liang, GS ;
Hammer, RE ;
Takaishi, K ;
Kuriyama, H ;
Evers, BM ;
Li, WP ;
Horton, JD ;
Goldstein, JL ;
Brown, MS .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (09) :2489-2498
[8]   Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis [J].
Engelking, LJ ;
Kuriyama, H ;
Hammer, RE ;
Horton, JD ;
Brown, MS ;
Goldstein, JL ;
Liang, G .
JOURNAL OF CLINICAL INVESTIGATION, 2004, 113 (08) :1168-1175
[9]   Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin [J].
Fullerton, Morgan D. ;
Galic, Sandra ;
Marcinko, Katarina ;
Sikkema, Sarah ;
Pulinilkunnil, Thomas ;
Chen, Zhi-Ping ;
O'Neill, Hayley M. ;
Ford, Rebecca J. ;
Palanivel, Rengasamy ;
O'Brien, Matthew ;
Hardie, D. Grahame ;
Macaulay, S. Lance ;
Schertzer, Jonathan D. ;
Dyck, Jason R. B. ;
van Denderen, Bryce J. ;
Kemp, Bruce E. ;
Steinberg, Gregory R. .
NATURE MEDICINE, 2013, 19 (12) :1649-1654
[10]   Protein sensors for membrane sterols [J].
Goldstein, JL ;
DeBose-Boyd, RA ;
Brown, MS .
CELL, 2006, 124 (01) :35-46