The glucocorticoid receptor controls hepatic dyslipidemia through Hes1

被引：120

作者：

Lemke, Ulrike ^{[1
]}

Krones-Herzig, Anja ^{[1
]}

Diaz, Mauricio Berriel ^{[1
]}

Narvekar, Prachiti ^{[1
]}

Ziegler, Anja ^{[1
]}

Vegiopoulos, Alexandros ^{[1
]}

Cato, Andrew C. B. ^{[2
]}

Bohl, Sebastian ^{[3
]}

Klingmueller, Ursula ^{[3
]}

Screaton, Robert A. ^{[4
]}

Mueller-Decker, Karin ^{[5
]}

Kersten, Sander ^{[6
]}

Herzig, Stephan ^{[1
]}

机构：

[1] German Canc Res Ctr Heidelberg, DKFZ ZMBH Alliance, Emmy Noether & Marie Curie Res Grp Mol Metab Cont, D-69120 Heidelberg, Germany

[2] Forschungszentrum Karlsruhe, Inst Toxicol & Genet, D-76344 Eggenstein Leopoldshafen, Germany

[3] German Canc Res Ctr Heidelberg, DKFZ ZMBH Alliance, Dept Syst Biol Signal Transduct, D-69120 Heidelberg, Germany

[4] Childrens Hosp Eastern Ontario, Apoptosis Res Ctr, Ottawa, ON K1H 8L1, Canada

[5] German Canc Res Ctr Heidelberg, Core Facil Tumor Models, D-69120 Heidelberg, Germany

[6] Wageningen Univ, Div Human Nutr, NL-6700 EV Wageningen, Netherlands

来源：

CELL METABOLISM | 2008年 / 8卷 / 03期

关键词：

D O I：

10.1016/j.cmet.2008.08.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Aberrant accumulation of lipids in the liver ("fatty liver" or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of liverfunction, the molecular mechanisms of fatty liver development remain largely enigmatic. Here we show that liver-specific disruption of glucocorticoid receptor (GR) action improves the steatotic phenotype in fatty liver mouse models and leads to the induction of transcriptional repressor hairy enhancer of split 1 (Hes1) gene expression. The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene. Genetic restoration of hepatic Hes1 levels in steatotic animals normalizes hepatic triglyceride (TG) levels. As glucocorticoid action is increased during starvation, myotonic dystrophy, and Cushing's syndrome, the inhibition of Hes1 through the GR might explain the fatty liver phenotype in these subjects.

引用

页码：212 / 223

页数：12

共 46 条

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