Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice.
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.
Bijland
Silvia
S
Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Pieterman
Elsbet J
EJ
Maas
Annemarie C E
AC
van der Hoorn
José W A
JW
van Erk
Marjan J
MJ
van Klinken
Jan B
JB
Havekes
Louis M
LM
van Dijk
Ko Willems
KW
Princen
Hans M G
HM
Rensen
Patrick C N
PC
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
D001055:Apolipoproteins B; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D011345:Fenofibrate