Published Online
on September 15, 2008

A more recent version of this article appeared on September 30, 2008

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Submitted on May 19, 2008
Accepted on August 4, 2008

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, and 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.

^* To whom correspondence should be addressed. E-mail: lrudel{at}wfubmc.edu.

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.

Key words: atherosclerosis • diabetes mellitus • fatty acids • inflammation • obesity

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