Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
 6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotinic acid (niacin) favorably affects very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and lipoprotein (a) (LP[a]) and increases high-density lipoprotein (HDL). Emerging data indicates vascular anti-inflammatory properties to additionally account for niacin's proven effects in cardiovascular disease. Recent evidence indicates that niacin acts on GPR109A and GPR109B (HM74A and HM74, respectively), receptors expressed in adipocytes and immune cells. In adipocytes, GPR109A activation reduces triglyceride (TG) lipolysis, resulting in decreased free fatty acid (FFA) mobilization to the liver. In humans, this mechanism has yet to be confirmed because the plasma FFA decrease is transient and is followed by a rebound increase in FFA levels. New evidence indicates niacin directly inhibits diacylglycerol acyltransferase 2 (DGAT2) isolated from human hepatocytes, resulting in accelerated hepatic apolipoprotein (apo)B degradation and decreased apoB secretion, thus explaining reductions in VLDL and LDL. This raises important questions as to whether stimulation of GPR109A in adipocytes or inhibition of DGAT2 in liver by niacin best explain the reduction in VLDL and LDL in dyslipidemic patients. Kinetic and in vitro studies indicate that niacin retards the hepatic catabolism of apoA-I but not liver scavenger receptor B1-mediated cholesterol esters, suggesting that niacin inhibits hepatic holoparticle HDL removal. Indeed, recent preliminary evidence suggests that niacin decreases surface expression of hepatic beta-chain of adenosine triphosphate synthase, which has been implicated in apoA-I/HDL holoparticle catabolism. GPR109A-mediated production of prostaglandin D2 in macrophages and Langerhan cells causes skin capillary vasodilation and explains, in part, niacin's effect on flushing. Development of niacin receptor agonists would, theoretically, result in adipocyte TG accumulation (and clinical adiposity) and increased flushing. This raises questions about niacin receptor agonists as therapeutic agents. Several niacin receptor agonists have been developed and patented, but their clinical effects have not been described. Future research is needed to determine whether niacin receptor agonists will demonstrate all the beneficial properties of nicotinic acid on atherosclerosis and without significant adverse effects.
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PMID:Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents? 1804 54

Niacin has long been used in the treatment of dyslipidemia and cardiovascular disease. Recent research on niacin has been focused on understanding the mechanism of action of niacin and preparation of safer niacin formulations. New findings indicate that niacin does the following: 1) it inhibits hepatic diacylglycerol acyltransferase 2, resulting in inhibition of triglyceride synthesis and decreased apolipoprotein B-containing lipoproteins; 2) it decreases the surface expression of hepatic adenosine triphosphate synthase beta-chain, leading to decreased holoparticle high-density lipoprotein catabolism and increased high-density lipoprotein levels; and 3) it increases redox potential in arterial endothelial cells, resulting in inhibition of redox-sensitive genes. Flushing, an adverse effect of niacin, results from niacin receptor GPR109A-mediated production of prostaglandin D2 and E2 via DP1 and EP2/4 receptors. DP1 receptor antagonist (laropiprant) attenuates the niacin flush. A reformulated preparation of extended-release niacin (Niaspan; Abbott, Abbott Park, IL) lowers flushing compared with an older Niaspan formulation. These advancements in niacin research have rejuvenated its use for the treatment of dyslipidemia and cardiovascular disease.
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PMID:Niacin: an old drug rejuvenated. 1908 Jul 27