Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
Copyright policy )Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
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 lackingcyp7a1on 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 thecyp7a1−/−. 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 incyp7a1−/−. APOE*3-Leiden mice as compared with APOE*3-Leiden mice (−34% and −35%, respectively).Cyp7a1deficiency 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 includingsrebf1.Conclusions—Cyp7a1deficiency 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.
- Leiden University Medical Center Netherlands
- Delft University of Technology Netherlands
Male, Biomedical Research, Unclassified drug, Physiology, Cholesterol 7alpha monooxygenase, Apolipoprotein E3, Cholesterol ester, Srebf1 gene, Ketone Bodies, Lipoproteins, VLDL, Gene, Animal tissue, Mice, Feces, Hyperlipoproteinemia Type III, Cholesterol 7α-hydroxylase, Bile acid synthesis, Vitamin E, Vitamin A, Cholesterol 7-alpha-Hydroxylase, Mice, Knockout, Feces level, Retinol, Messenger RNA, Cytochrome P450 isoenzyme, Lipid diet, Triacylglycerol blood level, Sterols, Cholesterol, Cholesterol blood level, Hyperlipidemia, Blood, Bile acid biosynthesis, Very low density lipoprotein, Liver, Apolipoprotein E3 (Leidein), Atherogenic diet, Female, Cholesterol Esters, Acyltransferase, Lipolysis, Sterol regulatory element binding protein 1, Dgat1 protein, mouse, Bile acid, Biosynthesis, Vitamin, Catalysis, Diacylglycerol acyltransferase, Bile Acids and Salts, Knockout mouse, Apolipoproteins E, Antioxidant activity, Genetics, Cholesterol metabolism, Animals, Animal model, Animal experiment, RNA, Messenger, Diacylglycerol O-Acyltransferase, Enzyme deficiency, Triglycerides, Crosses, Genetic, SREBP-1, Sterol, Apolipoproteins B, Cross breeding, Mouse mutant, Lipogenesis, Alpha tocopherol, Lipoprotein synthesis, Nonhuman, Lipid Metabolism, Lipid metabolism, Metabolism, Diet, Atherogenic, Gene expression, Controlled study, Acyltransferases
Male, Biomedical Research, Unclassified drug, Physiology, Cholesterol 7alpha monooxygenase, Apolipoprotein E3, Cholesterol ester, Srebf1 gene, Ketone Bodies, Lipoproteins, VLDL, Gene, Animal tissue, Mice, Feces, Hyperlipoproteinemia Type III, Cholesterol 7α-hydroxylase, Bile acid synthesis, Vitamin E, Vitamin A, Cholesterol 7-alpha-Hydroxylase, Mice, Knockout, Feces level, Retinol, Messenger RNA, Cytochrome P450 isoenzyme, Lipid diet, Triacylglycerol blood level, Sterols, Cholesterol, Cholesterol blood level, Hyperlipidemia, Blood, Bile acid biosynthesis, Very low density lipoprotein, Liver, Apolipoprotein E3 (Leidein), Atherogenic diet, Female, Cholesterol Esters, Acyltransferase, Lipolysis, Sterol regulatory element binding protein 1, Dgat1 protein, mouse, Bile acid, Biosynthesis, Vitamin, Catalysis, Diacylglycerol acyltransferase, Bile Acids and Salts, Knockout mouse, Apolipoproteins E, Antioxidant activity, Genetics, Cholesterol metabolism, Animals, Animal model, Animal experiment, RNA, Messenger, Diacylglycerol O-Acyltransferase, Enzyme deficiency, Triglycerides, Crosses, Genetic, SREBP-1, Sterol, Apolipoproteins B, Cross breeding, Mouse mutant, Lipogenesis, Alpha tocopherol, Lipoprotein synthesis, Nonhuman, Lipid Metabolism, Lipid metabolism, Metabolism, Diet, Atherogenic, Gene expression, Controlled study, Acyltransferases
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).21 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!