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Abstract
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.
Highlights
The hypolipidemic effect exerted by p,p'-tetramethylhexadecanedioic 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
hepatic nuclear factor (HNF)-4 displacement exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates is mediated by the peroxisome proliferators activated receptor (PPAR)
Since apolipoprotein C-I1I potently inhibits plasma triglyceride-rich lipoprotein catabolism due to inhibition of their intravascular lipolysis by lipoprotein lipase as well as their liver receptor-mediated uptake [10,11,12,13,14], and in light of the hyperlipoproteinemia induced in h-apoC-I1I transgenic mice [15, 16], or the hypotriglyceridemia induced in human [17] or animals [18] lacking apoC-I1I, a decrease in plasma apoC-III could account for the hypolipidemic effect exerted by these drugs
Summary
(Received for publication, October 24, 1994, and in revised form, March 27, 1995). From the Department of Human Nutrition and Metabolism, Hebrew University, Faculty of Medicine, Jerusalem 91120, Israel. Th e puta tiv e bind ing of PPAR, PPAR-RXR, or HNF-4-PPAR to t he rat (- 91/- 77) or human (- 87/- 66) apoC-III C3P element was st udied by gel shi ft using the concerned transcription factors translate d in vitro in rabb it reti culocyt es or expressed in tra ns fecte d Cos cells (Fig. 5). Th e binding affinity of th e human apoC -III C3P element to HNF- 4 or PPAR-RXR was determin ed by mobility shift analysis usin g la beled ha poC-III C3P ele ment and increasing conce ntrations of nonradioactive C3P in t he presence of Cos extracts derived from cells transfected with expression vectors for eithe r HNF- 4 or PPARRXR. Th ese binding experime nts t h us furth er indi cate that t ra ns criptiona l su ppression of th e ap oCIII gene by HDIPP may be medi ated by displ acem ent of HNF-4 from its ap oC-III response ele me nt by PPAR -RXR binding to thi s pr omoter eleme nt
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