Forkhead transcription factor Foxa2 activates genes involved in hepatic lipid metabolism and is regulated by insulin. Activation of Foxa2 in the liver leads to increased oxidation and secretion of fatty acids in the form of triacylglycerols (TAGs), a process impaired in type 2 diabetes. Here, we demonstrate that Foxa2 is coactivated by PPARgamma coactivator beta (Pgc-1beta). Adenoviral expression of Foxa2 and Pgc-1beta in livers of ob/ob mice results in decreased hepatic TAG content and increased plasma TAG concentrations. In addition, the concerted action of Foxa2/Pgc-1beta activates genes in mitochondrial beta oxidation and enhances fatty acid metabolism. Furthermore, Foxa2/Pgc-1beta induce the expression of microsomal transfer protein, thereby increasing apoB-containing VLDL secretion. This process is inhibited by insulin through a Foxa2-dependent mechanism. These data demonstrate that Foxa2/Pgc-1beta regulate hepatic lipid homeostasis by affecting the clearance rate of fatty acids through oxidation and/or secretion of lipids in response to insulin.
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