title: Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells.
abstract: The lipidation of apoA-I in liver greatly influences HDL biogenesis and plasma HDL levels by stabilizing the secreted apoA-I. Niacin is the most effective lipid-regulating agent clinically available to raise HDL. This study was undertaken to identify regulatory mechanisms of niacin action in hepatic lipidation of apoA-I, a critical event involved in HDL biogenesis. In cultured human hepatocytes (HepG2), niacin increased: association of apoA-I with phospholipids and cholesterol by 46% and 23% respectively, formation of lipid-poor single apoA-I molecule-containing particles up to ~2.4-fold, and pre β 1 and α migrating HDL particles. Niacin dose-dependently stimulated the cell efflux of phospholipid and cholesterol and increased transcription of ABCA1 gene and ABCA1 protein. Mutated DR4, a binding site for nuclear factor liver X receptor alpha (LXR α ) in the ABCA1 promoter, abolished niacin stimulatory effect. Further, knocking down LXR α or ABCA1 by RNA interference eliminated niacin-stimulated apoA-I lipidation. Niacin treatment did not change apoA-I gene expression. The present data indicate that niacin increases apoA-I lipidation by enhancing lipid efflux through a DR4-dependent transcription of ABCA1 gene in HepG2 cells. A stimulatory role of niacin in early hepatic formation of HDL particles suggests a new mechanism that contributes to niacin action to increase the stability of newly synthesized circulating HDL.
authors.affiliation: Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA. Electronic address: Linhuazh@hotmail.com.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
authors.forename: Vaijinath S
authors.initials: VS
authors.lastname: Kamanna
authors.affiliation: Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
authors.forename: Shobha H
authors.initials: SH
authors.lastname: Ganji
authors.affiliation: Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Xiong
authors.affiliation: Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA. Electronic address: Moti.Kashyap@va.gov.
authors.forename: Moti L
authors.initials: ML
authors.lastname: Kashyap
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D008076:Cholesterol, HDL / Q000096:biosynthesis*; D003470:Culture Media / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D053442:High-Density Lipoproteins, Pre-beta / Q000378:metabolism; D006801:Humans; D009068:Movement / Q000187:drug effects; D009525:Niacin / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D003470:Culture Media; D053442:High-Density Lipoproteins, Pre-beta; D010743:Phospholipids; D009525:Niacin