title: Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells.
abstract: The vitamin D metabolite 24,25-dihydroxyvitamin D3 (24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25-[OH]2D3 but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3 has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3 modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3 to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3 resulted in decreased peroxisome proliferator-activated receptor alpha (PPARα) expression and retinoid-X-receptor alpha (RXRα) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3 for 1-3 h induced PKCα activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-jun phosphorylation, an increase in AP-1-dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3 increased IL-1β, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3 elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function.
authors.affiliation: Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Wehmeier
authors.affiliation: Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Onstead-Haas
authors.affiliation: Department of MedicineBiochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Norman C W
authors.initials: NC
authors.lastname: Wong
authors.affiliation: Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA.
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
authors.affiliation: Division of EndocrinologyDiabetes, and Metabolism, Department of Medicine, University of Florida Jacksonville College of Medicine, Jacksonville, Florida, USA Michael.haas@jax.ufl.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000378:metabolism* / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D016632:Apolipoprotein A-I; D016207:Cytokines; D018836:Inflammation Mediators; D047493:PPAR alpha; D016755:Proto-Oncogene Proteins c-jun; D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; D018808:Transcription Factor AP-1; D015650:24,25-Dihydroxyvitamin D 3
keywords: activator protein 1; apolipoprotein A-I; cardiovascular disease; peroxisome proliferator-activated receptor α; vitamin D