Regulation of human apolipoprotein m gene expression by orphan and ligand-dependent nuclear receptors.
Apolipoprotein M (apoM) plays an important role in the biogenesis and the metabolism of anti-atherogenic HDL particles in plasma and is expressed primarily in the liver and the kidney. We investigated the role of hormone nuclear receptors in apoM gene regulation in hepatic cells. Overexpression via adenovirus-mediated gene transfer and siRNA-mediated gene silencing established that hepatocyte nuclear factor 4 (HNF-4) is an important regulator of apoM gene transcription in hepatic cells. apoM promoter deletion analysis combined with DNA affinity precipitation and chromatin immunoprecipitation assays revealed that HNF-4 binds to a hormone-response element (HRE) in the proximal apoM promoter (nucleotides -33 to -21). Mutagenesis of this HRE decreased basal hepatic apoM promoter activity to 10% of control and abolished the HNF4-mediated transactivation of the apoM promoter. In addition to HNF-4, homodimers of retinoid X receptor and heterodimers of retinoid X receptor with receptors for retinoic acid, thyroid hormone, fibrates (peroxisome proliferator-activated receptor), and oxysterols (liver X receptor) were shown to bind with different affinities to the proximal HRE in vitro and in vivo. Ligands of these receptors strongly induced human apoM gene transcription and apoM promoter activity in HepG2 cells, whereas mutations in the proximal HRE abolished this induction. These findings provide novel insights into the role of apoM in the regulation of HDL by steroid hormones and into the development of novel HDL-based therapies for diseases such as diabetes, obesity, metabolic syndrome, and coronary artery disease that affect a large proportion of the population in Western countries.
Mosialou
Ioanna
I
Department of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion 71003, Greece.
Zannis
Vassilis I
VI
Kardassis
Dimitris
D
D001053:Apolipoproteins / Q000096:biosynthesis* / Q000235:genetics; D000075243:Apolipoproteins M; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006728:Hormones / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D054834:Lipocalins; D008659:Metabolic Diseases / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology
C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D051557:Hepatocyte Nuclear Factor 4; D006728:Hormones; D054834:Lipocalins; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids