Niacin has been used for the treatment of dyslipidemia for the past half-century, acting as an agonist of the β-hydroxybutyrate receptor hydroxycarboxylic acid 2 (HCA2; aka GPR109a). However, the major unwanted side effect of niacin is cutaneous flushing, which is caused by activation of HCA2 receptors in Langerhans cells in the skin. Liu et al. hypothesized that activation of HCA1 in adipocytes by lactate also results in the inhibition of lipolysis, suggesting that agonists for HCA1 may be useful for the treatment of dyslipidemia. The low potency of lactate to activate HCA1, coupled with its fast turnover rate in vivo, render it an inadequate tool to study the biological role of lactate/HCA1 in vivo. Screening hydroxylated carboxylic acids identified 3-hydroxybenzoic acid (3-HBA) as an agonist for both HCA2 and HCA1, whereas 3,5-dihydroxybenzoic acid (3,5-DHBA) is a specific agonist for only HCA1 (EC50 ∼ 150 μM). 3,5-DHBA inhibits lipolysis in wild-type mouse adipocytes but not in HCA1-deficient adipocytes. Therefore, 3,5-DHBA is a useful tool for the in vivo study of HCA1 function, and it offers a base for further HCA1 agonist design for the treatment of dyslipidemia.
See article at J Pharmacol Exp Ther 2012, 341:794–801.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics