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Volume 270, Number 22, Issue of June 2, pp. 13470-13475, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Mode of Action of Peroxisome Proliferators as Hypolipidemic Drugs
SUPPRESSION OF APOLIPOPROTEIN C-III

Rachel Hertz, Janette Bishara-Shieban, and Jacob Bar-Tana

The hypolipidemic effect exerted by ,`-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. 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.



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J. Biol. Chem., July 19, 1996; 271(29): 17167 - 17173.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
D. Kardassis, M. Laccotripe, I. Talianidis, and V. Zannis
Transcriptional Regulation of the Genes Involved in Lipoprotein Transport : The Role of Proximal Promoters and Long-range Regulatory Elements and Factors in Apolipoprotein Gene Regulation
Hypertension, April 1, 1996; 27(4): 980 - 1008.
[Full Text]

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 J. Biol. Chem.Home page
T. Lemberger, Rég. Saladin, M. Vázquez, F.ço. Assimacopoulos, B. Staels, Béa. Desvergne, W. Wahli, and J. Auwerx
Expression of the Peroxisome Proliferator-activated Receptor alpha Gene Is Stimulated by Stress and Follows a Diurnal Rhythm
J. Biol. Chem., January 19, 1996; 271(3): 1764 - 1769.
[Abstract] [Full Text] [PDF]

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R. Hertz, M. Seckbach, M. M. Zakin, and J. Bar-Tana
Transcriptional Suppression of the Transferrin Gene by Hypolipidemic Peroxisome Proliferators
J. Biol. Chem., January 5, 1996; 271(1): 218 - 224.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
E. Raspe, H. Duez, P. Gervois, C. Fievet, J.-C. Fruchart, S. Besnard, J. Mariani, A. Tedgui, and B. Staels
Transcriptional Regulation of Apolipoprotein C-III Gene Expression by the Orphan Nuclear Receptor RORalpha
J. Biol. Chem., January 19, 2001; 276(4): 2865 - 2871.
[Abstract] [Full Text] [PDF]

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M. Elholm, I. Dam, C. Jorgensen, A.-M. Krogsdam, D. Holst, I. Kratchmarova, M. Gottlicher, J.-A. Gustafsson, R. Berge, T. Flatmark, et al.
Acyl-CoA Esters Antagonize the Effects of Ligands on Peroxisome Proliferator-activated Receptor alpha Conformation, DNA Binding, and Interaction with Co-factors
J. Biol. Chem., June 8, 2001; 276(24): 21410 - 21416.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
W. R. Oliver Jr., J. L. Shenk, M. R. Snaith, C. S. Russell, K. D. Plunket, N. L. Bodkin, M. C. Lewis, D. A. Winegar, M. L. Sznaidman, M. H. Lambert, et al.
A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport
PNAS, April 24, 2001; 98(9): 5306 - 5311.
[Abstract] [Full Text] [PDF]


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