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

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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).

Figure 1. Proposed mechanism underlying the side-effects seen with SCD1 inhibition

Under normal conditions, SCD1 catalyzes the conversion of saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), which are preferred substrates for esterification into cellular triglyceride (TG). It is reasonable to assume that many of the side-effects seen with SCD1 inhibition may stem from the abnormal accumulation of SCD1 substrates (SFA) in multiple tissues. SFAs are known to promote the activation of toll-like receptor 4 (TLR4) and drive inflammation. In the liver the accumulation of SFA promotes steatohepatitis in response to a methionine-choline-deficient diet. In the colon, the accumulation of SFA promotes DSS and bacterial-driven inflammatory colitis. In the pancreatic β-cell, the accumulation of SFA results in lipotoxicity and cell death. In the artery wall, the accumulation of SFA promotes TLR4 activation in macrophages and augments atherosclerosis. Importantly, dietary ω-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation can prevent the accelerated atherosclerosis seen with SCD1 inhibition in part by dampening inflammatory signaling in macrophages.