Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes

Abstract

The niacin receptor GPR109A is a Gi-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.

Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice

“…We observed response elements for RXR/FXR, several CCAAT/enhancer binding protein, HNF1, glucocorticoid receptor, SREBP-1 and -2, and four cAMP response elements in addition to others shown in supplementary Table I. Because it was impossible to test the role of all of them for the NA effect, we focused on the possible role of cAMP because it had been shown previously that NA reduces cAMP in the liver ( 46 ). cAMP stimulates HNF4 ␣ -phosphorylation, which has a lower DNA binding activity and may reduce transcriptional activation ( 47 ).…”

Biased Ligands for Better Cardiovascular Drugs

“…121 Early attempts to eliminate the flushing effect of niacin have centered on pharmacokinetics 122 and coformulation with prostaglandin inhibitors, 123 with marginal success in flush reduction in both cases. 114,123 Several groups have reported novel GPR109a agonists capable of causing free fatty acid reductions without induction of flush in mice; however, none of these compounds have been successfully developed to date.…”

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

“…It was also assumed that the beneficial effects of NA on plasma lipids are mediated via a receptor rather than a vitamin mechanism because of the high dose required (100-fold higher than that required to prevent pellagra) and the failure of NAM to provide similar benefits (Tunaru et al, 2003). Indeed, some evidence supports that GPR109A is necessary for NA to raise HDL cholesterol (Li et al, 2010; Tunaru et al, 2003). However, the absence of GRP109A expression in the liver (Soga et al, 2003; Tunaru et al, 2003; Wise et al, 2003), a central hub for HDL and LDL metabolism, also questions whether the effects of NA on blood lipids derive from GPR109A activation.…”