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

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-/-Apob100/100). 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 *Address 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. Tel: 336-716-2823; Fax: 336-716-6279; E-mail: [email protected]