Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation

• Published in: Journal of lipid research Vol. 53; no. 11; pp. 2380 - 2389
• Main Authors: Umemoto, Tomio, Subramanian, Savitha, Ding, Yilei, Goodspeed, Leela, Wang, Shari, Han, Chang Yeop, Teresa, Antonio Sta, Kim, Jinkyu, O'Brien, Kevin D., Chait, Alan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2012; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Adipose Tissue - drug effects; Adipose Tissue - immunology; Animals; Atherosclerosis - drug therapy; Atherosclerosis - immunology; Atherosclerosis - metabolism; Azetidines - therapeutic use; Cholesterol - metabolism; Ezetimibe; hepatic steatosis; Immunohistochemistry; Inflammation - drug therapy; Insulin Resistance; Intestinal Absorption - drug effects; Intestines; macrophage; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptors, LDL - genetics; Receptors, LDL - metabolism; Weight Gain - drug effects; macrophage; ezetimibe; insulin resistance; hepatic steatosis
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M029264

Adipose tissue inflammation is associated with insulin resistance and increased cardiovascular disease risk in obesity. We previously showed that addition of cholesterol to a diet rich in saturated fat and refined carbohydrate significantly worsens dyslipidemia, insulin resistance, adipose tissue macrophage accumulation, systemic inflammation, and atherosclerosis in LDL receptor-deficient (Ldlr−/−) mice. To test whether inhibition of intestinal cholesterol absorption would improve metabolic abnormalities and adipose tissue inflammation in obesity, we administered ezetimibe, a dietary and endogenous cholesterol absorption inhibitor, to Ldlr−/− mice fed chow or high-fat, high-sucrose (HFHS) diets without or with 0.15% cholesterol (HFHS+C). Ezetimibe blunted weight gain and markedly reduced plasma lipids in the HFHS+C group. Ezetimibe had no effect on glucose homeostasis or visceral adipose tissue macrophage gene expression in the HFHS+C fed mice, although circulating inflammatory markers serum amyloid A (SSA) and serum amyloid P (SSP) levels decreased. Nevertheless, ezetimibe treatment led to a striking (>85%) reduction in atherosclerotic lesion area with reduced lesion lipid and macrophage content in the HFHS+C group. Thus, in the presence of dietary cholesterol, ezetimibe did not improve adipose tissue inflammation in obese Ldlr−/− mice, but it led to a major reduction in atherosclerotic lesions associated with improved plasma lipids and lipoproteins.