26 We now show that FGF21 expression is increased in MED1ΔLiv mouse liver after PPARγ overexpression (Fig. 6B). This might suggest that FGF21-regulated inhibition of SREBP-1 and Y 27632 of other adipogenesis-related genes, such as adipsin, adiponectin, caveolin-1, and SMAF1, contribute to the attenuation of hepatic steatosis in MED1ΔLiv mouse following PPARγ overexpression (Fig. 6B). However, it is unclear as to how FGF21 levels are increased in

MED1ΔLiv mouse liver following PPARγ overexpression. FGF21 is regulated by both PPARγ and PPARα and because this regulation requires MED1 it is conceivable that other mechanism(s) also exist to maintain high FGF21 levels in MED1 null livers. In this study, we also report that other coactivators, namely SRC-1, PRIC285, PRIP, and PIMT, are not essential for PPARγ-induced adipogenic steatosis (Supporting Fig. 3). PPARγ stimulated hepatic steatosis in these

coactivator null mouse livers, indicating the redundancy of these coactivators in PPARγ function in vivo. Disruption of genes encoding for p160/SRC-1 family members (SRC-1, SRC-2, and SRC-3) singly, has been shown to be redundant for PPARα-regulated gene expression in mouse liver.17, 32 PRIC285, a component of PRIC complex, has been shown to interact with PPARα, PPARγ, TRβ1, ERα, and RXRα.33 PRIC285−/− mice showed no differences in the magnitude of pleiotropic responses when challenged with PPARα ligands, such as Wy-14,643 or ciprofibrate, implying Cabozantinib that PRIC285 is not essential for PPARα function.34 We now demonstrate that PRIC285 is also unnecessary for PPARγ function in liver. Coactivator PRIP (NCoA6) and its associated protein PIMT (NCoA6IP), function as linkers between the two major multiprotein complexes

anchored by CBP/p300 and MED1.35 PIMT interacts with coactivators CBP, p300, MED1, and PRIP in vivo and in vitro.35 PRIP-deficient mouse embryonic fibroblasts are refractory to PPARγ-stimulated 上海皓元 adipogenic conversion and fail to express adipogenic marker aP2, a PPARγ-responsive gene.36 However, surprisingly, our in vivo observations indicated the development of severe fatty liver in PRIPΔLiv and PIMTΔLiv mice following PPARγ overexpression. These results suggest that under in vivo conditions, MED1 absence results in a dominant phenotype as compared to PRIP deletion. The nonessential role of PRIP and PIMT in the PPARγ pathway may be due to the compensation between PRIP and PIMT in vivo. In conclusion, this study provides evidence that MED1 is required for high-fat diet–induced and PPARγ-induced hepatic steatosis and that loss of MED1 protects against fatty liver under these conditions. It is possible that expression levels of MED1 in liver might also play a significant role in the progression of fatty liver disease by modulating lipotoxicity and influencing steatohepatitis and endoplasmic reticulum stress.