Inhibition of Stearoyl-CoA Desaturase 1 (SCD1) Dissociates Insulin Resistance and Obesity From Atherosclerosis

Authors

J. Mark Brown, Wake Forest University
Soonkyu Chung, University of Nebraska-LincolnFollow
Janet K. Sawyer, Wake Forest UniversityFollow
Chiara Degirolamo, Wake Forest University
Heather M. Alger, Wake Forest University
Tam Nguyen, Wake Forest University
Xuewei Zhu, Wake Forest University
My-Ngan Duong, Wake Forest University
Amanda L. Wibley, Wake Forest University
Ramesh Shah, Wake Forest University
Matthew A. Davis, Wake Forest University
Kathryn Kelley, Wake Forest University
Martha D. Wilson, Wake Forest University
Carol Kent, Wake Forest University
John S. Parks, Wake Forest University
Lawrence L. Rudel, Wake Forest University

Document Type

Article

Date of this Version

2008

Citation

Circulation. 2008 September 30; 118(14): 1467–1475.

Comments

Used by permission

Abstract

Background—Stearoyl-CoA 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. However, unexpectedly 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, reduced plasma triglyceride, yet had little impact on LDL cholesterol. Since dietary SFAs have been shown to promote inflammation through toll-like receptor 4 (TLR4), we examined macrophage TLR4 function. Interestingly, SCD1 inhibition resulted in alterations in macrophage membrane lipid composition and marked hypersensitivity to TLR4 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.