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| Status |
Public on May 27, 2010 |
| Title |
Fenofibrate increases VLDL-triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
The PPARĪ± activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since 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%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) 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%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA 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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| Overall design |
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. After 4 hours fasting, livers were isolated and individual gene arrays were performed.
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| Contributor(s) |
Bijland S, Pieterman EJ, Maas AC, van der Hoorn JW, van Erk MJ, van Klinken JB, Havekes LM, Willems van Dijk K, Princen HM, Rensen PC |
| Citation(s) |
20501652 |
| Submission date |
Apr 05, 2010 |
| Last update date |
Jan 17, 2013 |
| Contact name |
Marijana Radonjic |
| E-mail(s) |
marijana.radonjic@tno.nl
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| Organization name |
TNO
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| Street address |
Utrechtseweg 48
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| City |
Zeist |
| ZIP/Postal code |
3704HE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL10288 |
Affymetrix GeneChip Mouse Genome 430 2.0 Array [CDF: Mm_ENTREZG_11] |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA126303 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE21211_RAW.tar |
47.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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