Stearoyl-CoA desaturase and insulin signaling - what is the molecular switch?
(2010)
Journal - Biochimica et biophysica acta
Abstract :
Increasing evidence suggests that stearoyl-CoA desaturase (SCD), the rate limiting enzyme of monounsaturated fatty acid biosynthesis, is an important factor in the pathogenesis of lipid-induced insulin resistance. Mice with a targeted disruption of the SCD1 gene have improved glucose tolerance compared to wild-type mice, despite lower fasting plasma insulin levels. Increased SCD activity has been found in insulin resistant humans and animals, whereas SCD1 deficiency attenuates both diet- and genetically- induced impairment of insulin action. Phosphorylation of serine and threonine residues on insulin receptor, insulin receptor substrates (IRS1 and IRS2), and on Akt has been shown to be the major step in insulin signaling that is altered due to the lack of SCD1. In this review we discuss perturbations in cell signaling and lipid metabolism cascades in insulin-sensitive tissues due to SCD1 deficiency. In particular, we address the role of cellular signaling molecules including free fatty acids, ceramides, fatty acid-CoAs, AMP-activated protein kinase, protein tyrosine phosphatase 1B as well as of membrane fluidity. While the precise mechanism of SCD action on insulin signaling remains to be clarified, current findings on SCD point to a very promising novel target for the treatment of insulin resistance.Copyright © 2010. Published by Elsevier B.V.
Novel substituted heteroaromatic compounds as inhibitors of stearoyl-CoA desaturase.
(2010)
Journal - Expert opinion on therapeutic patents
Abstract :
Stearoyl-CoA desaturase 1 (SCD1) has been implicated as a novel therapeutic target for the treatment of a variety of metabolic diseases, including diabetes, obesity, hepatic steatosis, atherosclerosis and cardiovascular disease. The application WO2009129625 from Merck Frosst Canada claims novel substituted heteroaromatic compounds as inhibitors of SCD and potential drugs for the pharmacological treatment of metabolic disorders, when used alone or in combination with other drugs. Based on in vitro activity of the patented compounds, these molecules may be considered as potential SCD inhibitors and could be of therapeutic value. However, further preclinical studies are needed to evaluate their curative potential and safety before clinical development.
Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin deficient mice.
(2010)
Journal - Journal of lipid research
Abstract :
The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using ob/ob;SCD1-/- mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle function in leptin deficiency. We show that disruption of SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and free fatty acids (FA). The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac free FA, diacylglycerol, TG and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1-/- mice compared to ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved left ventricle function in ob/ob mice caused by SCD1 deficiency.