| Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice. | |
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MedLine Citation:
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PMID: 20501652 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The peroxisome proliferator-activated receptor alpha (PPARalpha) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%) and TG (-60%) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles (-68%). This was associated with an increased post-heparin lipoprotein lipase (LPL) activity (+110%) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue, and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%) but not the VLDL-apolipoprotein B (apoB) production rate. Kinetic studies using [(3)H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma fatty acids and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. |
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Authors:
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Silvia Bijland; Elsbet J Pieterman; Annemarie C E Maas; José W A van der Hoorn; Marjan J van Erk; Jan B van Klinken; Louis M Havekes; Ko Willems van Dijk; Hans M G Princen; Patrick C N Rensen |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-25 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-09 Completed Date: 2010-08-30 Revised Date: 2011-08-25 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 25168-75 Citation Subset: IM |
Affiliation:
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Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apolipoproteins B / metabolism Fenofibrate / pharmacology* Humans Lipid Metabolism / drug effects Lipoproteins, HDL / metabolism Lipoproteins, VLDL / metabolism* Liver / drug effects, metabolism Male Mice Mice, Transgenic Triglycerides / blood*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Apolipoproteins B; 0/Lipoproteins, HDL; 0/Lipoproteins, VLDL; 0/Triglycerides; 0/very low density lipoprotein triglyceride; 49562-28-9/Fenofibrate |
| Comments/Corrections | |
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