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

Rachel Hertz, Vered Sheena, Bella Kalderon, Ina Berman, Jacob Bar-Tana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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 languageEnglish
Pages (from-to)1057-1062
Number of pages6
JournalBiochemical Pharmacology
Volume61
Issue number9
DOIs
StatePublished - 1 May 2001

Keywords

  • Apo C-III
  • Fibrates
  • Hypolipidemic drugs
  • Lipoproteins
  • Medica
  • PPARα

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