Journal
JOURNAL OF LIPID RESEARCH
Volume 53, Issue 11, Pages 2380-2389Publisher
ELSEVIER
DOI: 10.1194/jlr.M029264
Keywords
ezetimibe; insulin resistance; hepatic steatosis; macrophage
Categories
Funding
- National Institutes of Health [HL-094352, HL-092969, DK-035816]
- Merck
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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. -Umemoto, T., S. Subramanian, Y. Ding, L. Goodspeed, S. Wang, C. Y. Han, A. Sta. Teresa, J. Kim, K. D. O'Brien, and A. Chait. Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation. J. Lipid Res. 2012. 53: 2380-2389.
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