title: Opposite regulation of the human apolipoprotein M gene by hepatocyte nuclear factor 1 and Jun transcription factors.
abstract: HDL is a negative risk factor for atherosclerosis because of its multiple atheroprotective functions. Inflammation converts HDL particles from anti-atherogenic to pro-atherogenic, and this transformation is associated with changes in HDL structure and composition. Apolipoprotein M (apoM) has been recently shown to play a role in the maturation of HDL in plasma and to protect from atherosclerosis. ApoM gene is expressed primarily in the liver and kidney and is down-regulated by pro-inflammatory signals. We now show that the human apoM promoter harbors a dual specificity regulatory element in the proximal region that binds hepatocyte nuclear factor 1 (HNF-1) and members of the AP-1 family of pro-inflammatory transcription factors (c-Jun and JunB). Overexpression of c-Jun or JunB repressed both the basal and the HNF-1-mediated transactivation of the human apoM promoter. Treatment of HepG2 cells with potent inflammation-inducing phorbol esters or overexpression of PKCα was associated with a marked inhibition of apoM gene expression in a c-Jun/JunB-dependent manner. We provide evidence for a novel mechanism of inflammation-induced transcriptional repression that is based on the competition between HNF-1 and Jun proteins for binding to the same regulatory region. A similar mechanism accounts for the down-regulation of the liver-specific apolipoprotein A-II gene by Jun factors. Our studies provide novel insights on the mechanisms that control the expression of liver-specific apolipoprotein genes during inflammation and could affect the maturation and the functionality of HDL particles.
authors: Department of Basic Sciences, University of Crete Medical School, Heraklion 71003, Greece.
authors: Ioanna
authors: I
authors: Mosialou
authors: Konstantin
authors: K
authors: Krasagakis
authors: Dimitris
authors: D
authors: Kardassis
mesh_terms: D001053:Apolipoproteins / Q000378:metabolism*; D000075243:Apolipoproteins M; D002460:Cell Line; D008076:Cholesterol, HDL / Q000378:metabolism; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D054834:Lipocalins; D008954:Models, Biological; D009154:Mutation; D010703:Phorbol Esters / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D008076:Cholesterol, HDL; D054834:Lipocalins; D010703:Phorbol Esters; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051537:Hepatocyte Nuclear Factor 1