title: Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages.
abstract: Many of the beneficial and adverse effects of niacin are mediated via a G protein receptor, G protein-coupled receptor 109A/hydroxycarboxylic acid 2 receptor (GPR109A/HCA2), which is highly expressed in adipose tissue and macrophages. Here we demonstrate that immune activation increases GPR109A/HCA2 expression. Lipopolysaccharide (LPS), TNF, and interleukin (IL) 1 increase GPR109A/HCA2 expression 3- to 5-fold in adipose tissue. LPS also increased GPR109A/HCA2 mRNA levels 5.6-fold in spleen, a tissue rich in macrophages. In peritoneal macrophages and RAW cells, LPS increased GPR109A/HCA2 mRNA levels 20- to 80-fold. Zymosan, lipoteichoic acid, and polyinosine-polycytidylic acid, other Toll-like receptor activators, and TNF and IL-1 also increased GPR109A/HCA2 in macrophages. Inhibition of the myeloid differentiation factor 88 or TIR-domain-containing adaptor protein inducing IFNβ pathways both resulted in partial inhibition of LPS stimulation of GPR109A/HCA2, suggesting that LPS signals an increase in GPR109A/HCA2 expression by both pathways. Additionally, inhibition of NF-κB reduced the ability of LPS to increase GPR109A/HCA2 expression by ∼50% suggesting that both NF-κB and non-NF-κB pathways mediate the LPS effect. Finally, preventing the LPS-induced increase in GPR109A/HCA2 resulted in an increase in TG accumulation and the expression of enzymes that catalyze TG synthesis. These studies demonstrate that inflammation stimulates GPR109A/HCA2 and there are multiple intracellular signaling pathways that mediate this effect. The increase in GPR109A/HCA2 that accompanies macrophage activation inhibits the TG accumulation stimulated by macrophage activation.
authors.affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121.
authors.forename: Arthur
authors.initials: A
authors.lastname: Moser
authors.affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121.
authors.forename: Judy K
authors.initials: JK
authors.lastname: Shigenaga
authors.affiliation: Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121.
authors.forename: Carl
authors.initials: C
authors.lastname: Grunfeld
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016908:Gram-Positive Bacterial Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050152:Intra-Abdominal Fat / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009181:Mycoses / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C473652:Hcar2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic
keywords: G protein-coupled receptor 109A; G proteins; cytokines; diacylglycerol transferase; hydroxycarboxylic acid 2 receptor; lipopolysaccharide; triglycerides