Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol
Copyright policy )Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol
Objective— High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase ( Cyp7a1 ) catalyzes the rate-limiting step in the intrahepatic conversion of cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice. Methods and Results— Reduced bile acid biosynthesis in Cyp7a1−/− .APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma cholesterol levels, but the distribution of cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of cholesterol efflux from the liver to HDL. Conclusions— Strongly reduced bile acid synthesis in Cyp7a1−/− .APOE*3-Leiden mice leads to increased plasma HDL-cholesterol levels, as related to an increased hepatic expression of ABCA1.
- Leiden University Medical Center Netherlands
- Delft University of Technology Netherlands
- University of Lille France
Biomedical Research, Mouse, Physiology, Apolipoprotein E3, Low density lipoprotein, Mice, Transgenic, Bile acid, Intermediate density lipoprotein, Biosynthesis, Phospholipid transfer protein, Conhuman, Animal tissue, Gene Expression Regulation, Enzymologic, Bile Acids and Salts, Phosphatidylcholine-Sterol O-Acyltransferase, Mice, Transgenic mouse, Phosphatidylcholine sterol acyltransferase, cholesterol transport, Genetics, Bile acid synthesis, Cholesterol metabolism, Animals, Humans, Animal experiment, RNA, Messenger, Phospholipid Transfer Proteins, Cholesterol 7-alpha-Hydroxylase, High density lipoprotein cholesterol, Mice, Knockout, Mouse mutant, Phospholipid transfer protein, mouse, ABC transporter A1, Messenger RNA, Cholesterol, HDL, Catabolism, Cholesterol blood level, Metabolism, Very low density lipoprotein, Gene Expression Regulation, Liver, Protein expression, High-density lipoprotein, ATP-Binding Cassette Transporters, Female, ATP Binding Cassette Transporter 1
Biomedical Research, Mouse, Physiology, Apolipoprotein E3, Low density lipoprotein, Mice, Transgenic, Bile acid, Intermediate density lipoprotein, Biosynthesis, Phospholipid transfer protein, Conhuman, Animal tissue, Gene Expression Regulation, Enzymologic, Bile Acids and Salts, Phosphatidylcholine-Sterol O-Acyltransferase, Mice, Transgenic mouse, Phosphatidylcholine sterol acyltransferase, cholesterol transport, Genetics, Bile acid synthesis, Cholesterol metabolism, Animals, Humans, Animal experiment, RNA, Messenger, Phospholipid Transfer Proteins, Cholesterol 7-alpha-Hydroxylase, High density lipoprotein cholesterol, Mice, Knockout, Mouse mutant, Phospholipid transfer protein, mouse, ABC transporter A1, Messenger RNA, Cholesterol, HDL, Catabolism, Cholesterol blood level, Metabolism, Very low density lipoprotein, Gene Expression Regulation, Liver, Protein expression, High-density lipoprotein, ATP-Binding Cassette Transporters, Female, ATP Binding Cassette Transporter 1
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