Stearoyl-CoA desaturase 1: A potential target for non-alcoholic fatty liver disease?-perspective on emerging experimental evidence

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease and one of the leading causes of death. An unnamed disease has become a global epidemic disease of public health concern. This spectrum of diseases manifests itself with initial accumulation of excessive triglycerides (due to de novo lipogenesis) in the hepatocytes, leading to simple steatosis. Although its aetiology is multi-factorial, lifestyle changes (diet and physical activity) are considered to be the key thriving factors. In this context, high fructose consumption is associated with an increased risk for developing NAFLD in humans, while high-fructose feeding to experimental animals results in hepatic steatosis and non-alcoholic steatohepatitis, by increasing hepatic lipogenesis. Among several lipogenic genes, the endoplasmic reticulum-bound stearoyl-CoA desaturase 1 (SCD1) is the key determinant of triglycerides biosynthesis pathway, by providing monounsaturated fatty acids, through the incorporation of a double bond at the delta-9 position of saturated fatty acids, specifically, palmitic (C16:0) and stearic (C18:0) acids, yielding palmitoleic (C16:1) and oleic (C18:1) acids, respectively. Various experimental studies involving SCD1 gene knockout and diet-induced rodent models have demonstrated that SCD1 plays a key role in the development of NAFLD, by modulating hepatic lipogenesis and thus triglyceride accumulation in the liver. Several pharmacological and dietary intervention studies have shown the benefits of inhibiting hepatic SCD1 in the pathogenesis of NAFLD. In this review, we give an overview of SCD1 in NAFLD, based on the current experimental evidence and the translational applicability of SCD1 inhibition in human NAFLD conditions, besides discussing the limitations and way-forward.

Emerging pharmacological treatment options for MAFLD

“…ACC catalyses the carboxylation of acetyl-CoA to manolyl-CoA. 28 SCD1 catalyses the formation of monounsaturated fatty acids from saturated fatty acids 29 and unsaturated FA are esterified to produce TGs by DGAT1/2. 30 Hyperglycaemia induces hepatic fat accumulation contributing to ER stress signaling, progression of liver damage from simple steatosis to NASH and cirrhosis.…”

“…ACC catalyses the carboxylation of acetyl-CoA to manolyl-CoA. 28 SCD1 catalyses the formation of monounsaturated fatty acids from saturated fatty acids 29 and unsaturated FA are esterified to produce TGs by DGAT1/2. 30 …”

Advances and Emerging Therapies in the Treatment of Non-alcoholic Steatohepatitis

“…SCD-1 catalyses monounsaturated fatty acids, preferentially stearoyl (C18:0) and palmitoyl (C16:0) CoA using nicotinamide adenine dinucleotide phosphate, cytochrome b5 and associated cytochrome b5 reductase to yield oleic acid (C18:1) and palmitoleic acid (C16:1), respectively. 67,68 3β-arachidyl amido cholanoic acid (Aramchol; Galmed Pharmaceuticals Ltd, Tel Aviv, Israel) is an oral, liver-specific bile acid derivative that touchREVIEWS in Endocrinology partially antagonizes SCD-1 expression within the hepatic parenchyma, thereby reducing liver triglyceride burden. Animal models have shown histological improvements in both steatohepatitis activity indices and fibrosis.…”

A Single Nucleotide Polymorphism (rs3811792) Affecting Human SCD5 Promoter Activity Is Associated with Diabetes Mellitus

“…Two isoforms of SCDs have been identified in humans. Numerous studies have demonstrated the inevitable importance of stearoyl-CoA desaturase-1 (SCD1) in the metabolic and signaling pathways, making its role unquestionable in several prevalent human diseases, including obesity, diabetes, fatty liver, and cardiovascular diseases [ 11 , 12 , 13 , 14 , 15 ]. Much is known about the lipid-sensitive expression [ 16 , 17 , 18 , 19 , 20 , 21 ], rapid protein degradation [ 22 , 23 ], and complex transcriptional regulation [ 24 ] of SCD1.…”