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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:768.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesterol 7-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production

Sabine M. Post; Martine Groenendijk; Karianne Solaas; Patrick C. N. Rensen; Hans M. G. Princen

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.

Correspondence to Dr H. M. G. Princen, Gaubius Laboratory, TNO Prevention and Health, Department of Biomedical Research, Division of Vascular and Metabolic Diseases, PO Box 2215, 2301 CE Leiden, The Netherlands. 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 (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.

Key Words: bile acid biosynthesis • cholesterol 7-hydroxylase • mouse • SREBP-1 • triglycerides

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