title: The glucocorticoid receptor controls hepatic dyslipidemia through Hes1.
abstract: 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 liver function, 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.
authors.affiliation: Emmy Noether and Marie Curie Research Group Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lemke
authors.forename: Anja
authors.initials: A
authors.lastname: Krones-Herzig
authors.forename: Mauricio
authors.initials: M
authors.lastname: Berriel Diaz
authors.forename: Prachiti
authors.initials: P
authors.lastname: Narvekar
authors.forename: Anja
authors.initials: A
authors.lastname: Ziegler
authors.forename: Alexandros
authors.initials: A
authors.lastname: Vegiopoulos
authors.forename: Andrew C B
authors.initials: AC
authors.lastname: Cato
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bohl
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.forename: Robert A
authors.initials: RA
authors.lastname: Screaton
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig