Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.
The hypolipidemic effect exerted by beta,beta'-tetramethyl-hexadecanedioic acid (Medica 16) is accounted for by enhanced catabolism of plasma triglyceride-rich lipoproteins due to a decrease in plasma apolipoprotein C-III (Frenkel, B., Mayorek, N., Hertz, R., and Bar-Tana, J. (1988) J. Biol. Chem. 263, 8491-8497; Frenkel, B., Bishara-Shieban, J., and Bar-Tana, J. (1994) Biochem. J. 298, 409-414). Decrease in apolipoprotein C-III exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates (e.g. Medica 16, fibrate drugs) is shown here to result from suppression of apolipoprotein C-III gene expression. Transcriptional suppression of apolipoprotein C-III is due to transcriptional suppression of hepatic nuclear factor (HNF)-4 as well as displacement of HNF-4 from the apolipoprotein C-III promoter. HNF-4 displacement exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates is mediated by the peroxisome proliferators activated receptor (PPAR). Transcriptional suppression of HNF-4-enhanced genes (e.g. apolipoprotein C-III) along with transcriptional activation of peroxisomal and other genes by hypolipidemic drugs may account for their broad spectrum pharmacological effect.
Hertz
R
R
Department of Human Nutrition and Metabolism, Hebrew University, Faculty of Medicine, Jerusalem, Israel.
Bishara-Shieban
J
J
Bar-Tana
J
J
D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010169:Palmitic Acids / Q000494:pharmacology*; D010750:Phosphoproteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D000960:Hypolipidemic Agents; C403128:MLX protein, human; D009838:Oligodeoxyribonucleotides; D010169:Palmitic Acids; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; C056166:MEDICA 16