Key result
SCD1 inhibition protects against obesity and insulin resistance but accelerates aortic atherosclerosis in mice.
Why the study?
The role of stearoyl-coenzyme A desaturase 1 (SCD1) in lipoprotein metabolism and atherosclerosis progression was investigated to understand its impact on metabolic syndrome features and atherosclerosis.
Does SCD1 inhibition using antisense oligonucleotides affect atherosclerosis progression in a mouse model of hyperlipidemia?
Does SCD1 inhibition using antisense oligonucleotides affect atherosclerosis progression in a mouse model of hyperlipidemia?
SCD1 inhibition protects against metabolic syndrome features but paradoxically promotes atherosclerosis, suggesting it is not a safe therapeutic target.
SCD1 inhibition shows metabolic benefits in hyperlipidemic mice; leaves open effects on lipoprotein metabolism and atherosclerosis in humans.
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.
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Brown et al. (2008) studied Hyperlipidemia and atherosclerosis. Antisense oligonucleotides to inhibit SCD1 was evaluated on Atherosclerosis progression and metabolic syndrome parameters. Inhibition of SCD1 in a mouse model protected against diet-induced obesity and insulin resistance but strongly promoted aortic atherosclerosis.