Transcriptional repressor HES-1– a critical check-point in hepatic lipid homeostasis

Abstract

According to recent estimates of the World Health Organization the number of people diagnosed with diabetes type II – now 150 million worldwide – will double by 2025. While it is certain that a dysregulation of lipid metabolism contributes to the outbreak of the disease the molecular mechanisms are still unclear. The impaired lipid metabolism in the diabetic state largely depends on the aberrant activity of genes encoding metabolic key enzymes. Transcription factors involved in this gene regulation, however, are still mostly unknown. We identified the bHLH transcriptional repressor HES-1 as a novel regulatory switch and key determinant in normal hepatic lipid homeostasis. HES-1 suppresses insulin-regulated lipogenic programs through transcriptional repression of nuclear receptor peroxisome proliferator-activated receptor PPARγ1, a key regulator of lipogenesis (Herzig et al. Nature 426, 2003). This study aimed to explore the biological function of HES-1 for aberrant liver metabolism in the diabetic state. Our results demonstrated that in contrast to suppression of PPARγ1, HES-1 overexpression induced expression of the PPARγ2 isoform in liver, shifting the relative abundance of the two PPARγ isoforms towards the adipose-specific PPARγ2 type. Remarkably, an abnormal PPARγ1/PPARγ2 ratio is a hallmark of the insulin-resistant, steatotic liver in diabetes. Consistent with functional assays, chromatin-immunoprecipitation confirmed binding of HES-1 to PPARγ1 and PPARγ2 gene promoters in vivo. To elucidate the biological function of HES-1 for the manifestation of a diabetic gene expression profile and phenotype, RNAi adenoviruses were constructed and successfully tested for in vivo HES-1 gene knock-downs. Further studies using these constructs in diabetic mouse models will finally resolve the role of HES-1 in the development of hepatic dyslipidemia. Our studies could establish HES-1 as a novel target for therapeutic intervention and underline its role as a new candidate gene for type II diabetes susceptibility.