Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia producing a desirable normalization of a range of cardiovascular risk factors, including a marked elevation of high density lipoprotein and a reduction in mortality. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a G i -G proteincoupled receptor may contribute. Utilizing available information on the tissue distribution of nicotinic acid receptors, we identified candidate orphan receptors. The selected orphan receptors were screened for responses to nicotinic acid, in an assay for activation of G i -G proteins. Here we describe the identification of the G protein-coupled receptor HM74 as a low affinity receptor for nicotinic acid. We then describe the subsequent identification of HM74A in follow-up bioinformatics searches and demonstrate that it acts as a high affinity receptor for nicotinic acid and other compounds with related pharmacology. The discovery of HM74A as a molecular target for nicotinic acid may facilitate the discovery of superior drug molecules to treat dyslipidemia.

OBJECTIVE-Pharmacological use of peroxisome proliferatoractivated receptor (PPAR)␦ agonists and transgenic overexpression of PPAR␦ in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS-The, and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS-Treatment with GW501516showed statistically significant reductions in fasting plasma triglycerides (Ϫ30%), apolipoprotein B (Ϫ26%), LDL cholesterol (Ϫ23%), and insulin (Ϫ11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P Ͻ 0.05) and 30% reduction in urinary isoprostanes (P ϭ 0.01) were also observed. Except for a lowering of triglycerides (Ϫ30%, P Ͻ 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased (P Ͻ 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased.CONCLUSIONS-The PPAR␦ agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle. Diabetes 57: 332-339, 2008

No abstract

Objectives-Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)␦ expression. In parallel, PPAR␦ agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models. Methods and Results-Healthy volunteers were allocated placebo (nϭ6) or PPAR␦ agonist (GW501516) at 2.5 mg (nϭ9) or 10 mg (nϭ9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (Pϭ0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (Pϭ0.02). HDLc was enhanced in both treatment groups (2.5 mg Pϭ0.004, 10 mg PϽ0.001) when compared with the decrease in the placebo group (Ϫ11.5Ϯ1.6%, Pϭ0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (Pϭ0.002). However, LpL expression remained unchanged. Conclusions-This is the first report of a PPAR␦ agonist administered to man. In this small study, GW501516 significantly

Monocyte-endothelial interactions are of fundamental importance in determining the movement of monocytes from the blood stream into the vessel wall. This study reports that two endothelium-derived factors, nitric oxide and prostacyclin, alter in vitro monocyte behavior. Nitric oxide (>10~s M) inhibited monocyte adhesion to porcine aortic endothelial cell monolayers, whereas prostacyclin (10~9 to 10~5 M) had no effect Both nitric oxide and prostacyclin inhibited monocyte chemotaxis stimulated by /v-fonnyl-methionyl-leucyl-phenvlalanine and induced dose-dependent increases in intracellular cyclic guanosine monophosphate and cyclic adenosine monophosphate concentrations, respectively. The cell surface expression of the CDllb/CD18 adhesion receptor, a glycoprotein complex known to mediate monocyte intercellular adhesion, was not altered by either nitric oxide or by prostacyclin. Thus, endothelium-derived nitric oxide and prostacyclin may have a physiological role in modulating monocyte-vascular wall interactions. Alterations in this system may contribute to the increased monocyte emigration from the blood stream into the vessel wall observed in atherogenesis. (Arteriosclerosis and Thrombosis 1991;ll:254-260)M onocyte adhesion to endothelium and immigration into the vessel wall are believed to be important events during atherogenesis.1 These processes require the expression, on the cell surface, of functional adhesion glycoproteins of the CD11/CD18 integrin family, 2 of which the CDllb a-unit appears to be the most important. 3The factors that regulate monocyte emigration are poorly characterized although several endotheliumderived factors are reported to be monocyte/macrophage chemoattractants. -5 The endothelium releases other factors, including endothelium-derived relaxing factor (EDRF), known to be nitric oxide (NO), 6 and prostacyclin (PGI 2 ), which are both potent vasorelaxants. Received April 10, 1990; revision accepted November 22, 1990. aggregation 9 and adhesion, 10 thereby contributing to the antithrombotic surface that the endothelium presents to circulating platelets. PGI 2 acts on adenylate cyclase to increase intracellular cyclic adenosine monophosphate (cAMP) concentrations, 11 while NO raises cyclic guanosine monophosphate (cGMP) levels via its stimulation of soluble guanylate cyclase. 12This study reports the investigation of the effects of NO and PGI 2 on monocyte adhesion to endothelium and chemotaxis in response to the agonist, Af-formylmethionyl-leucyl-phenylalanine (fMLP) in vitro. To assess mechanisms by which these agents might exert their effect on monocytes, intracellular cyclic nucleotide concentrations and the surface expression of the CDllb/CD18 adhesion protein were measured.