Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.

Staels, B; Vu-Dac, N; Kosykh, V A; Saladin, R; Fruchart, J C; Dallongeville, J; Auwerx, J

doi:10.1172/jci117717

Cited by 410Lipid metabolism and disordersPeroxisome Proliferator-Activated ReceptorsCholesterol and Lipid Metabolism

Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.

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Staels, B, Vu-Dac, N, Kosykh, V A, Saladin, R, Fruchart, J C, Dallongeville, J, Auwerx, J·1995·Journal of Clinical Investigation

DOI 10.1172/jci117717PMC PMC295538

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Abstract

Epidemiological and transgenic animal studies have implicated apo C-III as a major determinant of plasma triglyceride metabolism. Since fibrates are very efficient in lowering triglycerides, it was investigated whether fibrates regulate apo C-III gene expression. Different fibrates lowered rat liver apo C-III mRNA levels up to 90% in a dose- and time-dependent manner, whereas intestinal apo C-III mRNA remained constant. This decrease in liver apo C-III mRNA was rapid (1 d) and reversible, since it was restored to control levels within 1 wk after cessation of treatment. In addition, fenofibrate treatment abolished the developmental rise of hepatic apo C-III mRNA observed during the suckling-weaning period. Administration of fibrates to rats induced liver and intestinal expression of the acyl CoA oxidase gene, the rate-limiting enzyme for peroxisomal beta-oxidation of fatty acids. In primary cultures of rat and human hepatocytes, fenofibric acid lowered apo C-III mRNA in a time- and dose-dependent manner. This reduction in apo C-III mRNA levels was accompanied by a decreased secretion of apo C-III in the culture medium of human hepatocytes. In rat hepatocytes fenofibric acid induced acyl CoA oxidase gene expression, whereas acyl CoA oxidase mRNA remained unchanged in human hepatocytes. Nuclear run-on and transient transfection experiments of a reporter construct driven by the human apo C-III gene promoter indicated that fibrates downregulate apo C-III gene expression at the transcriptional level. In conclusion, these studies demonstrate that fibrates decrease rat and human liver apo C-III gene expression. In humans the mechanisms appears to be independent of the induction of peroxisomal enzymes. This downregulation of liver apo C-III gene expression by fibrates may contribute to the hypotriglyceridemic action of these drugs.

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Activation of PPARα increases LPL and apo A-V, decreases apo C-III, thereby enhancing catabolism of TG-rich lipoproteins and reducing serum TG levels.
“Activation of PPARα increases the production of lipoprotein lipase (LPL) and apolipoprotein (apo) A-V, while it decreases the plasma levels of apo C-III that inhibits LPL activity, thereby enhancing the catabolism of TG-rich lipoproteins and reducing serum TG levels [31–34].”
From Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases (2020) · cites this paper as [34]

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Authors: Staels, B., Vu-Dac, N., Kosykh, V. A., Saladin, R., Fruchart, J. C., Dallongeville, J., & Auwerx, J.
Affiliations: Institut Pasteur de Lille (FR)
ORCID: Staels, B
Auwerx, J
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1995-02-01
Volume: 95
Issue: 2
Pages: 705-712
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci117717
PMC: PMC295538
OpenAlex: W2131037449
Cited by: 410
References: 59
Citations by year: 2026: 4 · 2025: 4 · 2024: 1 · 2023: 6 · 2022: 8 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 11 · 2017: 10 · 2016: 8 · 2015: 9 · 2014: 7 · 2013: 7 · 2012: 5
FWCI: 13.97
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords: fibrates, fenofibrate, fenofibric acid, apolipoprotein C-III, gene downregulation, hepatic gene expression, transcriptional regulation, hepatocytes
MeSH terms: Aging, Animals, Apolipoproteins C, Base Sequence, Cells, Cultured, Enzyme Induction, Female, Gene Expression Regulation, Humans, Kinetics, Liver, Male, Microbodies, Molecular Sequence Data, Oxidoreductases, Pregnancy, Prenatal Exposure Delayed Effects, Fenofibrate, Polymerase Chain Reaction, Rats, Wistar, DNA Primers, Acyl-CoA Oxidase, Rats, Apolipoprotein C-III

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Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.

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