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

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

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

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 (LDLrApob). 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.

Original languageEnglish (US)
Pages (from-to)1467-1475
Number of pages9
JournalCirculation
Volume118
Issue number14
DOIs
StatePublished - Sep 30 2008

Keywords

  • Atherosclerosis
  • Diabetes mellitus
  • Fatty acids
  • Inflammation
  • Obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Inhibition of Stearoyl-Coenzyme A Desaturase 1 Dissociates Insulin Resistance and Obesity from Atherosclerosis'. Together they form a unique fingerprint.

Cite this