| Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes. | |
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MedLine Citation:
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PMID: 20655299 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The niacin receptor GPR109A is a G(i)-protein-coupled receptor which mediates the effects of niacin on inhibiting intracellular triglyceride lipolysis in adipocytes. However, the role of GPR109A in mediating the effects of niacin on high density lipoprotein (HDL) metabolism is unclear. We found niacin has no effect on HDL-C in GPR109A knockout mice. Furthermore, niacin lowered intracellular cAMP in primary hepatocytes mediated by GPR109A. We used an adeno-associated viral (AAV) serotype 8 vector encoding GPR109A under the control of the hepatic-specific thyroxine-binding globulin promoter to specifically overexpress GPR109A in mouse liver. Plasma HDL-C, hepatic ABCA1 and the HDL cholesterol production rate were significantly reduced in mice overexpressing GPR109A. Overexpression of GPR109A reduced primary hepatocyte free cholesterol efflux to apoA-I; conversely, GPR109A deficient hepatocytes had increased ABCA1-mediated cholesterol efflux. These data support the concept that the HDL-C lowering effect of niacin in wild-type mice is mediated through stimulation of GPR109A in hepatocytes; such an effect then leads to reduced hepatocyte ABCA1 expression and activity, decreased cholesterol efflux to nascent apoA-I, and reduced HDL-C levels. These results indicate that niacin-mediated activation of GP109A in liver lowers ABCA1 expression leading to reduced hepatic cholesterol efflux to HDL. |
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Authors:
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Xiaoyu Li; John S Millar; Nicholas Brownell; François Briand; Daniel J Rader |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-07-22 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 80 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-09-20 Completed Date: 2010-10-06 Revised Date: 2012-04-20 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1450-7 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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metabolism Animals Apolipoprotein A-I / metabolism Cells, Cultured Cholesterol / metabolism Cholesterol, HDL / blood Cyclic AMP / metabolism Female Hepatocytes / metabolism* Lipopolysaccharides / pharmacology Lipoproteins, HDL / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Niacin / pharmacology Receptors, G-Protein-Coupled / physiology* Receptors, Nicotinic / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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P50 HL083799-04/HL/NHLBI NIH HHS; P50-HL-083799/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Apolipoprotein A-I; 0/Cholesterol, HDL; 0/Hcar2 protein, mouse; 0/Lipopolysaccharides; 0/Lipoproteins, HDL; 0/Receptors, G-Protein-Coupled; 0/Receptors, Nicotinic; 57-88-5/Cholesterol; 59-67-6/Niacin; 60-92-4/Cyclic AMP |
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