Original Paper Pathobiology 2002–03;70:215–218 DOI: 10.1159/000069332 Fatty Acid Bile Acid Conjugates Inhibit Atherosclerosis in the C57BL/6 Mouse Model A. Gonen a A. Shaish a A. Leikin-Frenkel b T. Gilat b,c D. Harats a a Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, and b Minerva Center for Cholesterol, Gallstones and Lipid Metabolism in the Liver, Sackler Faculty of Medicine, Tel Aviv University, and c Galmed Medical Research, Tel Aviv, Israel Received: M ay 13, 2002 Accepted: October 9, 2002 Dr. Dror Harats Institute of Lipid and Atherosclerosis Research Sheba Medical Center Tel Hashomer 52621 (Israel) Tel. +972 3 5302940, Fax +972 3 5343521, E-Mail dharats@post.tau.ac.il ABC Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com © 2003 S. Karger AG, Basel 1015–2008/03/0704–0215$19.50/0 Accessible online at: www.karger.com/pat Key Words Atherosclerosis W C57BL/6 m ice W Cholesterol W Fatty acid bile acid conjugates Abstract Objective: The aim of the current research was to study whether fatty acid bile acid conjugates (FABACs) have a beneficial effect on atherosclerosis progression and blood lipid levels in mice. M ethods: C57BL/6 fem ale mice, fed a high-fat Paigen diet, were administered an oral dose of FABAC or DDH 2 O daily. Quantification of atherosclerotic fatty-streak lesions at the aortic sinus was performed. Results: The FABAC-treated mice showed a significant reduction in the atherosclerotic lesion areas as compared to the control group (p = 0.019). A signifi- cant elevation in total cholesterol levels was observed in both the FABAC and control groups. Higher FABAC lev- els were measured in the high-density lipoprotein frac- tion as compared to the very-low-density and low-densi- ty lipoprotein fractions. Conclusion: Our findings demon- strate that FABACs, given orally, reduce the develop- ment of atherosclerosis in mice fed a high-fat high-cho- lesterol diet, despite a lack of effect on plasma lipid levels. Copyright © 2003 S. Karger AG, Basel Introduction Fatty acid bile acid conjugates (FABACs) are a new family of synthetic molecules designed to solubilize cho- lesterol in bile and blood. In vitro, they were shown to retard and prevent cholesterol crystallization in supersat- urated model lipid solutions and human bile [1]. FABACs were also shown to dissolve preexisting cholesterol crys- tals. In experimental animals, FABACs prevented choles- terol crystallization in gallbladder bile and dissolved preexisting crystals. In mice fed a lithogenic diet, FA- BACs prevented the formation of cholesterol gallstones [2] and dissolved preexisting cholesterol gallstones [3]. Atherosclerotic vascular disease is the major cause of mortality in Western societies, regardless of the recent advances in medical treatments. Atherosclerosis begins with the formation of fatty streaks, consisting of cholester- ol-laden macrophages known as foam cells, beneath the endothelial cells that line the arteries. This early lesion progresses to the more advanced fibrous plaque, which is characterized by the presence of smooth muscle cells. In advanced lesions, the core becomes necrotic and lipids are released into the intima, where cholesterol crystals may form [4]. While it is a complex and multifactorial disease, there is no doubt today that elevated plasma cholesterol levels play a dominant role in atherogenesis. Low-density lipoprotein (LDL) is the major carrier of cholesterol in