Transcription Coactivator Mediator Subunit MED1 Is Required for the Development of Fatty Liver in the Mouse

Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a nuclear receptor, when overexpressed in liver stimulates the induction of adipocyte-specific and lipogenesis-related genes and causes hepatic steatosis. We report here that Mediator 1 (MED1; also known as PBP or TRAP220), a key subunit of the Mediator complex, is required for high-fat diet-induced hepatic steatosis as well as PPAR gamma-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPAR gamma and other transcriptional activators. Liver-specific MED1 knockout (MED1(Delta Liv)) mice, when fed a high-fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1(Delta Liv) mice injected with adenovirus-PPAR gamma (Ad/PPAR gamma) by tail vein also did not develop fatty liver, whereas mice with MED1 (MED1(fl/fl)) fed a high-fat diet or injected with Ad/PPAR gamma developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPAR gamma-injected mouse livers showed impaired induction in MED1(Delta Liv) mouse liver of adipogenic markers, such as aP2, adipsin, adiponectin, and lipid droplet-associated genes, including caveolin-1, CideA, S3-12, and others. These adipocyte-specific and lipogenesis-related genes are strongly induced in MED1(fl/fl) mouse liver in response to Ad/PPAR gamma. Re-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1(Delta Liv) mouse liver restored PPAR gamma-stimulated hepatic adipogenic response. These studies also demonstrate that disruption of genes encoding other coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect on hepatic adipogenesis induced by PPAR gamma overexpression. Conclusion: We conclude that transcription coactivator MED1 is required for high-fat diet-induced and PPAR gamma-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;53:1164-1174)