Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Prize 2006

Dr. Ulrike Lemke und Dr. Stephan Herzig

Department of Molecular Metabolic Control, German Cancer Research Center Heidelberg

Glucocorticoids promote fatty liver development through dual track inhibition of transcriptional repressor Hes-1

Aberrant hepatic fat accumulation ("fatty liver") represents a pathophysiological hallmark of obesity, extensive fasting or glucocorticoid therapy. Elevated glucocorticoid levels under these conditions are causative for the fatty liver phenotype, although the molecular mechanisms of their action remain largely enigmatic. Here we show that glucocorticoids inhibit hepatic expression of transcriptional repressor hairy enhancer of split-1 (Hes-1) which had been previously identified as an anti-lipogenic factor in the liver.

In fatty liver mouse models, progressively declining Hes-1 levels correlated with increasing hepatic lipid stores; and, genetic restoration of hepatic Hes-1 gene expression in obese mice normalized hepatic triglyceride levels and improved systemic insulin sensitivity. Mechanistic in vivo Hes-1 promoter analysis demonstrated that glucocorticoid exposure of hepatocytes leads to the disassembly of trans-activator complexes and the simultaneous recruitment of inhibitory factors, including cAMP-dependent transcription factor CREB and its co-activator acetyl- transferase P300 or transcriptional repressor I?B?, respectively. Inhibition of Hes-1 provides a molecular rationale for glucocorticoid-induced fatty liver development.

Restoration of Hes-1 activity might, therefore, represent an attractive approach in the treatment of obesity, insulin resistance and as an adjunctive scheme during glucocorticoid therapy.



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