title: Transcription coactivator mediator subunit MED1 is required for the development of fatty liver in the mouse.
abstract: Peroxisome proliferator-activated receptor-γ (PPARγ), 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 PPARγ-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPARγ and other transcriptional activators. Liver-specific MED1 knockout (MED1(ΔLiv) ) mice, when fed a high-fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1(ΔLiv) mice injected with adenovirus-PPARγ (Ad/PPARγ) 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/PPARγ developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPARγ-injected mouse livers showed impaired induction in MED1(ΔLiv) 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/PPARγ. Re-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1(ΔLiv) mouse liver restored PPARγ-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 PPARγ overexpression.
  
  
  CONCLUSIONS
  We conclude that transcription coactivator MED1 is required for high-fat diet-induced and PPARγ-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;).
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL; Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Bai
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Huang
authors.forename: Aurore
authors.initials: A
authors.lastname: Vluggens
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Wolins
authors.forename: Nadereh
authors.initials: N
authors.lastname: Jafari
authors.forename: M Sambasiva
authors.initials: MS
authors.lastname: Rao
authors.forename: Jayme
authors.initials: J
authors.lastname: Borensztajn
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000209:etiology*; D020869:Gene Expression Profiling; D005809:Genes, Regulator; D056913:Mediator Complex Subunit 1 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D047495:PPAR gamma / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: D004041:Dietary Fats; D056913:Mediator Complex Subunit 1; D047495:PPAR gamma