TY  - GEN
Y1  - 2007///
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7758/
KW  - glucocorticoids 
KW  -  fatty liver 
KW  -  Hes-1 
KW  -  lipid metabolism
AV  - public
ID  - heidok7758
N2  - Aberrant hepatic fat accumulation (?fatty liver?) represents a pathophysiological hallmark of obesity and is associated with extended glucocorticoid therapy, obesity, Type II diabetes, and starvation. Elevated glucocorticoid levels under these conditions are causative for the fatty liver phenotype, although the molecular mechanisms of their action remain largely unclear.  This study demonstrates that glucocorticoids (GCs) promote fatty liver development through facilitated fat transport into the liver and not due to increased de novo fat synthesis. Transient knock-down of hepatic GR was associated with decreased hepatic gene expression of the fat transporters CD36 and caveolin 1 and with decreased expression of peroxisome proliferation-activating receptor gamma (PPARgamma) ? a transcription factor promoting CD36 and caveolin expression.  Moreover, glucocorticoids inhibited hepatic expression of transcriptional repressor Hairy and Enhancer of Split-1 (Hes-1) a previously identified anti-lipogenic factor. In fatty liver mouse models characterized by elevated GC levels diminished Hes-1 levels correlated with increased hepatic lipid stores. Genetic restoration of hepatic Hes-1 levels in obese mice normalized hepatic triglyceride levels and improved systemic insulin sensitivity. In mice injected with GCs for three weeks, genetically restored hepatic Hes-1 levels inhibited GC-induced liver fat accumulation. In both models, sustained Hes-1 was accompanied by increased oxidative consumption of triglycerides and decreased fat import into the liver. Hes-1 re-expression inhibited hepatic PPARgamma, CD36 and caveolin expression resembling effects in mice with transient GR knockdown. Loss of function analysis in primary hepatocytes confirmed PPARgamma and Cav1 as Hes-1 target genes. The data suggest that Hes-1 antagonizes GR-mediated transcriptional regulation of fat transport programs in the liver. Mechanistically, glucocorticoid exposure of hepatocytes lead to the disassembly of a cAMP-dependent CREB transactivator complex on the proximal Hes-1 gene promoter. The glucocorticoid receptor was shown here to decrease intracellular P-CREB levels and to interact with CREB via the bZIP domain of CREB. Furthermore, GR associated to glucocorticoid response elements in the proximal Hes-1 promoter region. Inhibition of hepatic Hes-1 provides a rationale for glucocorticoid-induced fatty liver development. Restoration of Hes-1 activity might, therefore, represent a new approach in the treatment of Non-Alcoholic Fatty Liver Disease and its associated complications such as hepatic insulin resistance. 
TI  - The role of transcriptional repressor Hes-1 in glucocorticoid-mediated fatty liver development
A1  - Lemke, Ulrike
ER  -