Suppression of hepatocyte nuclear factor-4α by acyl-CoA thioesters of hypolipidemic peroxisome proliferators

Hepatocyte nuclear factor-4 alpha (HNF-4 alpha) modulates the expression of liver-specific genes that control the production (e.g. apolipoprotein [apo] A-I and apo B) and clearance (e.g. apo C-m) of plasma lipoproteins. We reported that the CoA thioesters of amphipathic carboxylic hypolipidemic drugs (e.g. clofibric acid analogues currently used for treating hyperlipidemia in humans and substituted long-chain dicarboxylic acids) were formed in vivo, bound to HNF-4 alpha, inhibited its transcriptional activity, and suppressed the expression of HNF-4 alpha -responsive genes. Hypolipidemic PPAR alpha (peroxisome proliferator-activated receptor alpha) activators that were not endogenously thioesterified into their respective acyl-CoAs were shown to be effective in rats but not in humans, implying that the hypolipidemic activity transduced by PPAR alpha in rats was PPAR alpha -independent in humans. The suppressed acyl-CoA synthase of PPAR alpha knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4 alpha pathway to the hypolipidemic effect of PPAR alpha agonists in rodents. Hence, suppression of HNF-4 alpha activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPAR alpha activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPAR alpha and HNF-4 alpha pathways, respectively. (C) 2001 Elsevier Science Inc. All rights reserved.