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

Hepatocyte nuclear factor-4alpha (HNF-4alpha) 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-III) 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-4alpha, inhibited its transcriptional activity, and suppressed the expression of HNF-4alpha-responsive genes. Hypolipidemic PPARalpha (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 PPARalpha in rats was PPARalpha-independent in humans. The suppressed acyl-CoA synthase of PPARalpha knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4alpha pathway to the hypolipidemic effect of PPARalpha agonists in rodents. Hence, suppression of HNF-4alpha activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPARalpha activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPARalpha and HNF-4alpha pathways, respectively.