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Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice
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2010
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| Author: |
Bijland, S.
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Pieterman, E.J.
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Maas, A.C.E.
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Hoorn, J.W.A. van der
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Erk, M.J. van
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Klinken, J.B. van
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Havekes, L.M.
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Dijk, K.W. van
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Princen, H.M.G.
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Rensen, P.C.N.
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| 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
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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.
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[Abstract]
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Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
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2004
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| Author: |
Post, S.M.
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Groenendijk, M.
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Solaas, K.
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Rensen, P.C.N.
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Princen, H.M.G.
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| Keywords: |
Biology · Biomedical Research · Bile acid biosynthesis · Cholesterol 7α-hydroxylase · SREBP-1 · Bile acid · Cholesterol · Cholesterol 7alpha monooxygenase · Cholesterol ester · Cytochrome P450 isoenzyme · Messenger RNA · Sterol · Sterol regulatory element binding protein 1 · Unclassified drug · Very low density lipoprotein · Vitamin · Acyltransferase · Alpha tocopherol · Apolipoprotein E3 (Leidein) · Dgat1 protein, mouse · Diacylglycerol acyltransferase · Retinol · Animal experiment · Animal model · Animal tissue · Antioxidant activity · Bile acid synthesis · Catalysis · Cholesterol blood level · Cholesterol metabolism · Controlled study · Enzyme deficiency · Feces level · Gene · Gene expression · Hyperlipidemia · Knockout mouse · Lipid diet · Lipid metabolism · Lipogenesis · Lipoprotein synthesis · Nonhuman · Srebf1 gene · Triacylglycerol blood level · Atherogenic diet · Biosynthesis · Blood · Cross breeding · Feces · Genetics · Metabolism · Mouse mutant · Physiology · Acyltransferases · Animals · Apolipoprotein E3 · Apolipoproteins B · Apolipoproteins E · Bile Acids and Salts · Cholesterol 7-alpha-Hydroxylase · Cholesterol Esters · Crosses, Genetic · Diacylglycerol O-Acyltransferase · Diet, Atherogenic · Feces · Female · Hyperlipoproteinemia Type III · Ketone Bodies · Lipid Metabolism · Lipolysis · Lipoproteins, VLDL · Liver · Male · Mice · Mice, Knockout · RNA, Messenger · Sterols · Triglycerides · Vitamin A · Vitamin E
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Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/- APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-.APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. Conclusions-Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels. Chemicals / CAS: cholesterol 7alpha monooxygenase, 9037-53-0; cholesterol, 57-88-5; acyltransferase, 9012-30-0, 9054-54-0; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; diacylglycerol acyltransferase, 9029-98-5; retinol, 68-26-8, 82445-97-4; Acyltransferases, EC 2.3.-; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol Esters; Dgat1 protein, mouse, EC 2.3.1.20; Diacylglycerol O-Acyltransferase, EC 2.3.1.20; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4
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[Abstract]
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