on February 12, 2004
Published online before print February 12, 2004, doi: 10.1161/01.ATV.0000121572.21122.59
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Submitted on September 10, 2003
Accepted on January 20, 2004
Cholesterol 7
-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production
Sabine M. Post ;
From TNO Prevention and Health (S.M.P., M.G., K.S., P.C.N.R., H.M.G.P.), Gaubius Laboratory, Leiden, The Netherlands; and the Department of General Internal Medicine (P.C.N.R.), Leiden University Medical Center, Leiden, The Netherlands.
* To whom correspondence should be addressed. E-mail: jmg.princen{at}pg.tno.nl.
Objective--Cholesterol 7
-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 (VDLD)-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.
Key words: bile acid biosynthesis • cholesterol 7
-hydroxylase •
mouse •
SREBP-1 •
triglycerides
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