Suppression of hepatocyte nuclear factor-4 alpha by acyl-CoA thioesters ofhypolipidemic 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 re ported that the CoA thioesters of amphipathic carboxylic hypolipidemic drug s (e.g. clofibric acid analogues currently used for treating hyperlipidemia in humans and substituted long-chain dicarboxylic acids) were formed in vi vo, bound to HNF-4 alpha, inhibited its transcriptional activity, and suppr essed the expression of HNF-4 alpha -responsive genes. Hypolipidemic PPAR a lpha (peroxisome proliferator-activated receptor alpha) activators that wer e not endogenously thioesterified into their respective acyl-CoAs were show n to be effective in rats but not in humans, implying that the hypolipidemi c activity transduced by PPAR alpha in rats was PPAR alpha -independent in humans. The suppressed acyl-CoA synthase of PPAR alpha knockout mice left u nresolved 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 o f PPAR alpha activation by their respective free carboxylates. The hypolipi demic activity of peroxisome proliferators is mediated in rats and humans b y the PPAR alpha and HNF-4 alpha pathways, respectively. (C) 2001 Elsevier Science Inc. All rights reserved.