Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis.
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.


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.
Brown
J Mark
JM
Department of Pathology, Wake Forest University School of Medicine, Section on Lipid Sciences, Winston-Salem, NC 27157-1040, USA.
Chung
Soonkyu
S
Sawyer
Janet K
JK
Degirolamo
Chiara
C
Alger
Heather M
HM
Nguyen
Tam
T
Zhu
Xuewei
X
Duong
My-Ngan
MN
Wibley
Amanda L
AL
Shah
Ramesh
R
Davis
Matthew A
MA
Kelley
Kathryn
K
Wilson
Martha D
MD
Kent
Carol
C
Parks
John S
JS
Rudel
Lawrence L
LL
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
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