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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:685.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Dietary Cholesterol Worsens Adipose Tissue Macrophage Accumulation and Atherosclerosis in Obese LDL Receptor–Deficient Mice

Savitha Subramanian; Chang Yeop Han; Tsuyoshi Chiba; Timothy S. McMillen; Shari A. Wang; Antonio Haw, III; Elizabeth A. Kirk; Kevin D. O’Brien; Alan Chait

From the Departments of Medicine (S.S., C.Y.H., T.C., T.S.M., S.A.W., A.H., K.D.O., A.C.) and Pathobiology (E.A.K.), University of Washington, Seattle.

Correspondence to Alan Chait, MD, Department of Medicine, Box 356426, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6426. E-mail achait{at}u.washington.edu

Abstract

Objective— Chronic systemic inflammation accompanies obesity and predicts development of cardiovascular disease. Dietary cholesterol has been shown to increase inflammation and atherosclerosis in LDL receptor–deficient (LDLR^–/–) mice. This study was undertaken to determine whether dietary cholesterol and obesity have additive effects on inflammation and atherosclerosis.

Methods and Results— LDLR^–/– mice were fed chow, high-fat, high-carbohydrate (diabetogenic) diets without (DD) or with added cholesterol (DDC) for 24 weeks. Effects on adipose tissue, inflammatory markers, and atherosclerosis were studied. Despite similar weight gain between DD and DDC groups, addition of dietary cholesterol increased insulin resistance relative to DD. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were observed in intraabdominal adipose tissue in DD and DDC, but were significantly higher in the DDC group. Circulating levels of the inflammatory protein serum amyloid A (SAA) were 4.4-fold higher in DD animals and 15-fold higher in DDC animals than controls, suggesting chronic systemic inflammation. Hepatic SAA mRNA levels were similarly elevated. Atherosclerosis was increased in the DD-fed animals and further increased in the DDC group.

Conclusions— Obesity-induced macrophage accumulation in adipose tissue is exacerbated by dietary cholesterol. These local inflammatory changes in adipose tissue are associated with insulin resistance, systemic inflammation, and increased atherosclerosis in this mouse model.

The role of dietary cholesterol has been controversial. Here we show that cholesterol added to a diet rich in saturated fat and carbohydrates increases macrophage accumulation in adipose tissue, worsens insulin resistance, induces a heightened state of chronic inflammation, and increases atherosclerosis in LDLR^–/– mice.

Key Words: atherosclerosis • inflammation • obesity • lipoproteins • diet