title: Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation.
abstract: 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.
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, USA.
authors.forename: Tomio
authors.initials: T
authors.lastname: Umemoto
authors.forename: Savitha
authors.initials: S
authors.lastname: Subramanian
authors.forename: Yilei
authors.initials: Y
authors.lastname: Ding
authors.forename: Leela
authors.initials: L
authors.lastname: Goodspeed
authors.forename: Shari
authors.initials: S
authors.lastname: Wang
authors.forename: Chang Yeop
authors.initials: CY
authors.lastname: Han
authors.forename: Antonio Sta
authors.initials: AS
authors.lastname: Teresa
authors.forename: Jinkyu
authors.initials: J
authors.lastname: Kim
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000276:immunology*; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D001384:Azetidines / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy*; D007333:Insulin Resistance; D007408:Intestinal Absorption / Q000187:drug effects*; D007422:Intestines; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D001384:Azetidines; D011973:Receptors, LDL; D002784:Cholesterol; D000069438:Ezetimibe