Regulation of hepatic lipid homeostasis by transcriptional co-factor complexes

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In mammals, storage of fat in adipose tissue is essential for the maintenance of energy homeostasis. In contrast, aberrant accumulation of lipids in the liver (“fatty liver”) represents a hallmark of the Metabolic Syndrome and is tightly associated with malign obesity and type II diabetes. While fatty liver has been connected with numerous abnormalities of liver function, the molecular mechanisms of fatty liver development remain largely enigmatic. To this end, our recent studies have identified the WD40 transcriptional co-repressor TBL1 as a novel regulator of hepatic lipid metabolism and uncovered TBL1’s dysregulation in diabetic fatty liver mouse models. Based on our preliminary data we will therefore test to which extent TBL1 is functionally implicated in the switch between benign and malign obesity and hepatic dyslipidemia, and whether its regulatory role can be partly compensated by highly related co-repressor proteins. We expect to define a novel transcriptional control level of hepatic energy homeostasis, potentially triggering dysfunctional energy metabolism in diet-dependent, malign obesity and type II diabetes. The molecular characterization of TBL1-associated co-repressor complexes may, thereby, provide novel susceptibility genes for these severe metabolic disorders.