Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery

The metabolic syndrome has become a leading health concern in developed countries. In the search for strategies to combat this growing problem, stearoyl-CoA desaturase 1 (SCD1) inhibition has been proposed as an attractive therapeutic strategy. However, recent studies warn of potentially harmful consequences of SCD1 inhibition. The purpose of this review is to discuss recent insights into the potential for SCD1 inhibitors as viable metabolic syndrome therapeutics. SCD1 converts saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs). Although SCD1 inhibition protects against diet-induced obesity, hepatic steatosis, and insulin resistance, recent studies have demonstrated that the accumulation of SCD1 substrates (SFA) can promote inflammation, atherosclerosis, steatohepatitis, and pancreatic beta cell dysfunction in preclinical rodent models. This suggests SCD1 may play a critical role in suppressing inflammatory diseases by shuttling proinflammatory SFAs into less biologically active MUFA-enriched neutral lipids. Given this, SCD1 inhibitors given in conjunction with anti-inflammatory agents may provide a useful strategy to prevent the metabolic syndrome without deleterious side-effects seen with SCD1 inhibition alone. SCD1 inhibitors continue to hold promise as metabolic syndrome therapeutics; yet consideration must be taken to avoid the proinflammatory side-effects secondary to accumulation SCD1 substrates (SFAs).