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Transcription coactivator PBP/MED1 deficiency prevents dexamethasone‐induced fatty liver
Author(s) -
Jia Yuzhi,
Yu Songtao,
Rao M Sambasiva,
Reddy Janardan K
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a226-a
Subject(s) - steatosis , coactivator , endocrinology , medicine , glucocorticoid receptor , nuclear receptor , biology , fatty liver , peroxisome proliferator activated receptor , receptor , mediator , wild type , transcription factor , glucocorticoid , gene , mutant , biochemistry , disease
Peroxisome proliferators‐activated receptor‐binding protein (PBP) serves as an anchor for mediator transcription complex. Liver specific disruption of PBP gene results in near abrogation of PPARα and CAR nuclear receptor functions. Since CAR is regulated by glucocorticoid receptor (GR) we decided to test the hypothesis that deficiency of PBP affects GR target gene transcription leading to reduced CAR function. Dexamethasone induces fatty liver through GR regulated pathway. We report that targeted deletion of PBP in liver cells (PBP Liv‐/‐ ) results in the abrogation of Dex‐induced hepatic steatosis. After 3 days of Dex treatment (50 mg/kg i.p), macrovesicular hepatic steatosis developed in wild type mice but not in PBP Liv‐/‐ mice. On immunoblotting, long‐, medium‐, and short‐chain dehydrogenases located in mitochondrial matrix were found to be inhibited by Dex in wild type mouse liver, whereas Dex treatment failed to inhibit these enzymes in PBP Liv‐/‐ mice. CYP2B10, CYP3A11, CYP2C29 and CYP3A13 gene expressions were increased as assessed by qPCR, in wild type Dex treated mice as compared to PBP Liv‐/‐ mice. Basal GR mRNA levels in liver were same in wild type and PBP Liv‐/‐ mice and these levels did not differ after Dex treatment. We conclude that transcription coactivator PBP/MED1 is necessary for GR transcriptional activity and of CAR function. Down regulation of CAR in PBP liver nulls is related to GR function. Thus, PBP plays a crucial role in the transcriptional activity several nuclear receptors and in the pathogenesis of Dex‐induced hepatic steatosis. (This work was supported by NIH).