Abstract
Hepatocyte nuclear factor-4α (HNF-4α) 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-4α, inhibited its transcriptional activity, and suppressed the expression of HNF-4α-responsive genes. Hypolipidemic PPARα (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 PPARα in rats was PPARα-independent in humans. The suppressed acyl-CoA synthase of PPARα knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4α pathway to the hypolipidemic effect of PPARα agonists in rodents. Hence, suppression of HNF-4α activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPARα activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPARα and HNF-4α pathways, respectively.
Original language | English |
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Pages (from-to) | 1057-1062 |
Number of pages | 6 |
Journal | Biochemical Pharmacology |
Volume | 61 |
Issue number | 9 |
DOIs | |
State | Published - 1 May 2001 |
Keywords
- Apo C-III
- Fibrates
- Hypolipidemic drugs
- Lipoproteins
- Medica
- PPARα