CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance

被引：127

作者：

Cantley, Jennifer L. ^{[1
,2
]}

Yoshimura, Toru ^{[2
]}

Camporez, Joao Paulo G. ^{[2
]}

Zhang, Dongyan ^{[1
,2
]}

Jornayvaz, Francois R. ^{[2
]}

Kumashiro, Naoki ^{[1
,2
]}

Guebre-Egziabher, Fitsum ^{[2
]}

Jurczak, Michael J. ^{[2
]}

Kahn, Mario ^{[1
,2
]}

Guigni, Blas A. ^{[1
,2
]}

Serr, Julie ^{[2
]}

Hankin, Joseph ^{[4
]}

Murphy, Robert C. ^{[4
]}

Cline, Gary W. ^{[1
,2
]}

Bhanot, Sanjay ^{[5
]}

Manchem, Vara Prasad ^{[5
]}

Brown, J. Mark ^{[6
]}

Samuel, Varman T. ^{[2
]}

Shulman, Gerald I. ^{[1
,2
,3
]}

机构：

[1] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

[2] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA

[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[4] Univ Colorado, Sch Med, Dept Pharmacol, Denver, CO 80045 USA

[5] ISIS Pharmaceut, Carlsbad, CA 92010 USA

[6] Wake Forest Sch Med, Dept Pathol, Winston Salem, NC 27157 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 05期

基金：

美国国家卫生研究院;

关键词：

nonalcoholic fatty liver disease; type; 2; diabetes; FATTY LIVER-DISEASE; ADIPOSE TRIGLYCERIDE LIPASE; KINASE-C-EPSILON; CERAMIDE SYNTHESIS; ENERGY-METABOLISM; PROTEIN; MECHANISM; OBESITY; MICE; ACTIVATION;

D O I：

10.1073/pnas.1219456110

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：

Comparative gene identification 58 (CGI-58) is a lipid droplet-associated protein that promotes the hydrolysis of triglyceride by activating adipose triglyceride lipase. Loss-of-function mutations in CGI-58 in humans lead to Chanarin-Dorfman syndrome, a condition in which triglyceride accumulates in various tissues, including the skin, liver, muscle, and intestines. Therefore, without adequate CGI-58 expression, lipids are stored rather than used for fuel, signaling intermediates, and membrane biosynthesis. CGI-58 knockdown in mice using antisense oligonucleotide (ASO) treatment also leads to severe hepatic steatosis as well as increased hepatocellular diacylglycerol (DAG) content, a well-documented trigger of insulin resistance. Surprisingly, CGI-58 knockdown mice remain insulin-sensitive, seemingly dissociating DAG from the development of insulin resistance. Therefore, we sought to determine the mechanism responsible for this paradox. Hyperinsulinemic-euglycemic clamp studies reveal that the maintenance of insulin sensitivity with CGI-58 ASO treatment could entirely be attributed to protection from lipid-induced hepatic insulin resistance, despite the apparent lipotoxic conditions. Analysis of the cellular compartmentation of DAG revealed that DAG increased in the membrane fraction of high fat-fed mice, leading to PKC epsilon activation and hepatic insulin resistance. However, DAG increased in lipid droplets or lipid-associated endoplasmic reticulum rather than the membrane of CGI-58 ASO-treated mice, and thus prevented PKC epsilon translocation to the plasma membrane and induction of insulin resistance. Taken together, these results explain the disassociation of hepatic steatosis and DAG accumulation from hepatic insulin resistance in CGI-58 ASO-treated mice, and highlight the importance of intracellular compartmentation of DAG in causing lipotoxicity and hepatic insulin resistance.

引用

页码：1869 / 1874

页数：6