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(Circulation. 2008;118:1467-1475.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Inhibition of Stearoyl-Coenzyme A Desaturase 1 Dissociates Insulin Resistance and Obesity From Atherosclerosis

J. Mark Brown, PhD; Soonkyu Chung, PhD; Janet K. Sawyer, MS; Chiara Degirolamo, PhD; Heather M. Alger, BS; Tam Nguyen, BS; Xuewei Zhu, PhD; My-Ngan Duong, PhD; Amanda L. Wibley, BA; Ramesh Shah, MS; Matthew A. Davis, MS; Kathryn Kelley, MS; Martha D. Wilson, PhD; Carol Kent, BS; John S. Parks, PhD; Lawrence L. Rudel, PhD

From the Department of Pathology, Section on Lipid Sciences (J.M.B., S.C., J.K.S., C.D., T.N., X.Z., M.-N.D., R.S., M.A.D., K.K., M.D.W., C.K., J.S.P., L.L.R.), Department of Biochemistry (H.M.A.), and Department of Molecular Medicine (A.L.W.), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Lawrence L. Rudel, Wake Forest University School of Medicine, Department of Pathology, Section on Lipid Sciences, Medical Center Blvd, Winston-Salem, NC 27157–1040. E-mail lrudel{at}wfubmc.edu

Received May 19, 2008; accepted August 4, 2008.

Background— Stearoyl-coenzyme A desaturase 1 (SCD1) is a well-known enhancer of the metabolic syndrome. The purpose of the present study was to investigate the role of SCD1 in lipoprotein metabolism and atherosclerosis progression.

Methods and Results— Antisense oligonucleotides were used to inhibit SCD1 in a mouse model of hyperlipidemia and atherosclerosis (LDLr^–/–Apob^100/100). In agreement with previous reports, inhibition of SCD1 protected against diet-induced obesity, insulin resistance, and hepatic steatosis. Unexpectedly, however, SCD1 inhibition strongly promoted aortic atherosclerosis, which could not be reversed by dietary oleate. Further analyses revealed that SCD1 inhibition promoted accumulation of saturated fatty acids in plasma and tissues and reduced plasma triglyceride, yet had little impact on low-density lipoprotein cholesterol. Because dietary saturated fatty acids have been shown to promote inflammation through toll-like receptor 4, we examined macrophage toll-like receptor 4 function. Interestingly, SCD1 inhibition resulted in alterations in macrophage membrane lipid composition and marked hypersensitivity to toll-like receptor 4 agonists.

Conclusions— This study demonstrates that atherosclerosis can occur independently of obesity and insulin resistance and argues against SCD1 inhibition as a safe therapeutic target for the metabolic syndrome.

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CLINICAL PERSPECTIVE

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