Glucocorticoids promote fatty liver development through the repressor Hes-1

The occurrence of a fatty liver phenotype is closely linked to elevated glucocorticoid levels as associated with obesity, extensive fasting or glucocorticoid therapy. However, despite its clinical importance, the molecular determinants of glucocorticoid-induced fatty liver development remain largely enigmatic.

Consequently, we aimed to explore the transcriptional mechanisms of glucocorticoid-dependent fatty liver pathophysiology.

Our results showed that glucocorticoids inhibit hepatic protein expression and promoter activity of transcriptional repressor Hes-1 which had been previously identified by us as a cAMP-inducible anti-lipogenic factor in the liver. Using extensively fasted mice as a model for fatty liver development, we demonstrated that hepatic Hes-1 mRNA levels progressively declined with extended fasting correlating with elevated hepatic lipid accumulation. Indeed, genetic restoration of hepatic Hes-1 gene expression during long-term fasting via adenovirus-mediated gene transfer normalized hepatic triglyceride levels and systemic insulin sensitivity. Molecular Hes-1 promoter analysis demonstrated that glucocorticoids interfered with Hes-1 gene activity via two distinct mechanisms. On the one hand, glucocorticoids abolished phosphorylation of cAMP-dependent transcription factor CREB leading to release of CREB co-activator acetyltransferase P300 from the Hes-1 promoter and, subsequently, to diminished promoter histone acetylation. In addition, glucocorticoids were also shown to interfere with Hes-1 expression through the induction of transcriptional repressor IkappaB and its subsequent recruitment to the Hes-1 promoter.

Increased glucocorticoid action promotes insulin resistance. The inhibition of the anti-lipogenic Hes-1 repressor through these hormones, thereby, provides a molecular rational for the fatty liver phenotype in insulin-resistant patients. Restoration of Hes-1 activity might, thereby, represent an attractive approach in the treatment of the metabolic syndrome and pave the way to novel adjunctive therapies.