MODE OF ACTION OF PEROXISOME PROLIFERATORS AS HYPOLIPIDEMIC DRUGS - SUPPRESSION OF APOLIPOPROTEIN C-III

The hypolipidemic effect exerted by beta,beta'-tetramethyl-hexadecaned ioic acid (Medica 16) is accounted for by enhanced catabolism of plasm a triglyceride-rich lipoproteins due to a decrease in plasma apolipopr otein C-III (Frenkel, B., Mayorek, N., Hertz, R., and Bar-Tana, J. (19 88) J. Biol. Chem. 263, 8491-8497; Frenkel, B., Bishara-Shieban, J., a nd Bar-Tana, J. (1994) Biochem. J. 298, 409-414). Decrease in apolipop rotein C-III exerted by peroxisome proliferators/hypolipidemic amphipa thic carboxylates (e.g. Medica 16, fibrate drugs) is shown here to res ult from suppression of apolipoprotein C-III gene expression. Transcri ptional 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 ex erted by peroxisome proliferators/hypolipidemic amphipathic carboxylat es is mediated by the peroxisome proliferators activated receptor (PPA R). Transcriptional suppression of HNF-4-enhanced genes (e.g. apolipop rotein C-III) along with transcriptional activation of peroxisomal and other genes by hypolipidemic drugs may account for their broad spectr um pharmacological effect.