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Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice

Author: Bijland, S. · Pieterman, E.J. · Maas, A.C.E. · Hoorn, J.W.A. van der · Erk, M.J. van · Klinken, J.B. van · Havekes, L.M. · Dijk, K.W. van · Princen, H.M.G. · Rensen, P.C.N.
Type:article
Date:2010
Institution: TNO Kwaliteit van Leven
Source:Journal of Biological Chemistry, 33, 285, 25168-25175
Identifier: 409284
Keywords: Biology · Biomedical Research · Apolipoprotein B (apoB) · Emulsion particles · Fenofibrate · Hepatic genes · Kinetic study · Lipoprotein lipase · Lipoprotein metabolism · Male mouse · Mouse models · Palmitic acid · Peroxisome proliferator-activated receptor · Plasma cholesterol · Plasma triglycerides · Production rates · Skeletal muscle · Very low density lipoproteins · White adipose tissues · Acids · Cytology · Emulsification · Fatty acids · Gene expression · Glycerol · Liver · Mammals · Nutrition · Plasmas · Acetyl coenzyme A acetyltransferase · Acyl coenzyme A desaturase 1 · Acyl coenzyme A oxidase · Apolipoprotein A4 · Apolipoprotein B · Apolipoprotein B messenger RNA editing enzyme catalytic polypeptide 1 · Apolipoprotein C1 · Apolipoprotein C2 · Apolipoprotein C3 · Apolipoprotein E3 · Blood clotting factor 5 Leiden · Carnitine palmitoyltransferase I · Cholesterol · Cholesterol ester transfer protein · Diacylglycerol acyltransferase 1 · Diacylglycerol acyltransferase 2 · Fas antigen · Fatty acid · Fatty acid binding protein 2 · Fenofibrate · Lipoprotein lipase · Palmitic acid · Sterol regulatory element binding protein 1a · Sterol regulatory element binding protein 1c · Triacylglycerol · Triolein · Tritium · Animal experiment · Controlled study · Emulsion · Enzyme activity · Esterification · Food intake · Gene expression profiling · Lipid transport · Lipogenesis · Lipoprotein synthesis · Liver parenchyma · Nnhuman · Skeletal muscle · Treatment duration · Treatment outcome · Animals · Apolipoproteins B · Lipid Metabolism · Lipoproteins, HDL · Lipoproteins, VLDL · Liver · Male · Mice · Mice, Transgenic · Procetofen · Triglycerides · Biomedical Innovation · Healthy Living

Abstract

The peroxisome proliferator-activated receptor alpha (PPARα) 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 halflife of glycerol tri[<sup>3</sup>H]oleate-labeled VLDL-like emulsion particles (-68%). This was associated with an increased postheparin 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 [ <sup>3</sup>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. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.