Transcription coactivator mediator subunit MED1 is required for the development of fatty liver in the mouse.

ABSTRACT: Peroxisome proliferator-activated receptor-? (PPAR?), 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?-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPAR? and other transcriptional activators. Liver-specific MED1 knockout (MED1(?Liv) ) mice, when fed a high-fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1(?Liv) mice injected with adenovirus-PPAR? (Ad/PPAR?) 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? developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPAR?-injected mouse livers showed impaired induction in MED1(?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?. Re-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1(?Liv) mouse liver restored PPAR?-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? overexpression.We conclude that transcription coactivator MED1 is required for high-fat diet-induced and PPAR?-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;).

SUBMITTER: Bai L 

PROVIDER: S-EPMC3076129 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature