Stearoyl‐CoA desaturase: a new therapeutic target of liver steatosis

Abstract

AbstractStearoyl‐CoA desaturase (SCD) is the rate limiting enzyme catalyzing the biosynthesis of monounsaturated fatty acids, mainly oleate and palmitoleoate, which are used as substrates for the synthesis of triglycerides, wax esters, cholesterol esters, and phospholipids. Recent studies have shown that SCD1, the main SCD isoform expressed in liver, is a key player in the regulation of lipid metabolism. SCD1 deficient mice have increased energy expenditure, reduced body adiposity, increased insulin sensitivity and are resistant to diet‐induced obesity and liver steatosis. SCD1 was found to be specifically repressed during leptin‐mediated weight loss and leptin‐deficient ob/ob mice lacking SCD1 showed markedly reduced adiposity, despite higher food intake. In addition, SCD1 deficiency completely corrects the hypometabolic phenotype and hepatic steatosis of ob/ob mice, and attenuates fasting‐induced liver steatosis in peroxisome proliferator‐activated receptor‐α – deficient mice. Consequently, increased SCD activity has been found in humans and animals which accumulate significant amounts of lipids in liver, whereas SCD1 deficiency ameliorates both high‐fat diet induced and genetically induced hepatic steatosis. Much evidence indicates that the direct anti‐steatotic effect of SCD1 deficiency stems from increased fatty acid oxidation and reduced lipid synthesis. In this review we discuss our current understanding of the role of SCD1 in regulation of hepatic lipid partitioning and test the hypothesis that pharmacological manipulation of SCD might be of benefit in the treatment of non‐alcoholic fatty liver disease. Drug Dev. Res. 67:643–650, 2006. © 2006 Wiley‐Liss, Inc.