Disease relevance of Scd1

• A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity [1].
• Stearoyl-CoA desaturase (SCD)1 catalyzes the rate-limiting reaction of monounsaturated fatty acid (MUFA) synthesis and plays an important role in the development of obesity [2].
• Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferator-activated receptor-alpha [3].
• Stearoyl-CoA desaturase (SCD) has recently been shown to be a critical control point of lipid partitioning and body weight regulation [4].
• Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss [5].
• Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver [6].
• This study suggests hepatic SCD1 plays a key role in prevention of steatohepatitis by partitioning excess lipid into MUFA that can be safely stored [7].

High impact information on Scd1

• These transcription factors coordinate the expression of genes involved in creating and maintaining the adipocyte phenotype including the insulin-responsive glucose transporter (GLUT4), stearoyl CoA desaturase 1 (SCD1), and the fatty acid binding protein (422/aP2) [8].
• Scd1 is expressed in sebaceous glands and is disrupted in the asebia mouse [9].
• Thus, Scd1 is required for the onset of diet-induced hepatic insulin resistance [10].
• Treatment of mice with SCD1 ASOs resulted in prevention of diet-induced obesity with concomitant reductions in SCD1 expression and the ratio of oleate to stearoyl-CoA in tissues and plasma [11].
• In the current study, we tested the efficacy of pharmacological inhibition of SCD1 in controlling lipogenesis and body weight in mice [11].

Chemical compound and disease context of Scd1

• Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation [12].
• 8. It is concluded that increased substrate supply as a result of hyperphagia and not low concentration of linoleic acid is the main factor causing high acyl-CoA desaturase activity in obese mice [13].
• SCD1 also has been shown to be a key target of the anorexigenic hormone leptin, thus underscoring the importance of this enzyme, and consequently the cellular stearate-to-oleate ratio, in lipid metabolism and potentially in the treatment of obesity and related disorders [14].
• The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1(-/-) mice is indicative of cholestasis [15].
• Daily injections of 15 micrograms triiodothyronine (T3)/100 g body weight to hypothyroid mice resulted in repression of SCD1 mRNA levels by more than 50% in 48 hours and up to 65% in 6 days [16].

Biological context of Scd1

• However, in Scd1(-/-) mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1beta levels are markedly reduced [17].
• Intracerebroventricular leptin improves glucose homeostasis by improving insulin signal transduction in liver, but in this case the effect appears to be independent of SCD-1 [1].
• Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms [18].
• The SCD1 mutation increased the phosphorylation of both AMP-activated protein kinase and acetyl-CoA carboxylase, thereby increasing CPT activity and stimulating the oxidation of liver palmitoyl-CoA in the PPARalpha null mice [3].
• In contrast, the protein level of phosphatidylethanolamine N-methyltransferase, an enzyme involved in PC synthesis via methylation of phosphatidylethanolamine, was decreased by 80% in the liver of Scd1-/- mice [19].

Anatomical context of Scd1

• Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1(-/-) mice [17].
• The incorporation of [(3)H]glycerol into PC was increased by 2.5-fold in Scd1-/- primary hepatocytes compared with those of wild type mice [19].
• Immunoblot analyses demonstrated that twice as much CCTalpha was associated with plasma membrane in livers of Scd1-/- compared with wild type mice, suggesting that Scd1 mutation leads to an increase in CCT membrane affinity [19].
• Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle [4].
• beta-Amyloid-specific upregulation of stearoyl coenzyme A desaturase-1 in macrophages [20].

Associations of Scd1 with chemical compounds

• Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1(-/-) mice [17].
• Stearoyl-CoA desaturase (SCD) synthesizes oleate necessary for the biosynthesis of triglycerides and other lipids [18].
• Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids, which are required for normal rates of synthesis of triglycerides, cholesterol esters, and phospholipids [3].
• Our observations demonstrated that oleate produced by SCD is necessary for fructose-mediated induction of lipogenic gene expression through SREBP-1c-dependent and -independent mechanisms and suggested that SCD1 gene expression is important in lipid and carbohydrate homeostasis [18].
• Previously, we showed that Scd1 deficiency reduces liver triglyceride accumulation and considerably decreases synthesis of very low density lipoprotein and its secretion in both lean and obese mice [19].

Regulatory relationships of Scd1

• Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c [2].
• Scd3 is expressed in the skin of young asebia mutant mice (Scd1(ab2J)/Scd1(ab2J)) in the absence of Scd1 [21].
• Our studies indicate that the transcription of the human SCD gene is repressed by polyunsaturated fatty acids and cholesterol and that SREBP plays a role in the transcriptional activation of this gene [22].
• An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation [23].
• Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle [24].

Other interactions of Scd1

• The SCD1 deficiency rescued hepatic steatosis of the PPARalpha(-/-) mice [3].
• The promoter sequence of Scd3 reveals similarity with Scd1 in the proximal region but also possesses several distinctive features including the polyunsaturated fatty acid-response element [21].
• Previously, two members of this gene family, namely, Scd1 and Scd2, have been reported [21].
• The lipogenic diet fed to mice with a null mutation in the SCD1 gene (SCD-/-) fails to induce the synthesis of triglycerides in liver, despite the induction of expression of SREBP-1 and its target genes, fatty acid synthase and glycerol-3-phosphate acyltransferase [25].
• The content of phosphatidylcholine (PC) was increased by 40% and the activities of CTP:choline cytidylyltransferase (CCT), the rate-limiting enzyme in de novo PC synthesis, and choline phosphotransferase were increased by 64 and 53%, respectively, in liver of Scd1-/- mice [19].

Analytical, diagnostic and therapeutic context of Scd1

• By haplotype analysis and direct sequencing of PCR products, we show that this mutation is a new allele of the asebia locus with a naturally occurring mutation in the Scd1 gene (a CCC insertion at nucleotide position 835 in exon 5), which codes for stearoyl-CoA desaturase 1 [26].
• Furthermore, when the fat-free diet was supplemented with triacylglycerides containing polyunsaturated fatty acids, the transcription of the SCD1 gene and the induction of the SCD1 mRNA were significantly blunted [27].
• Northern blot analysis revealed that SCD1 mRNA levels were markedly higher than that in control kidneys [28].
• In control mice, constitutive renal SCD1 expression was low; however, TO-901317 treatment markedly increased SCD1 expression in the outer stripe of the outer medulla as assessed by both in situ hybridization and immunostain [28].
• The Northern blot and RT-PCR analyses showed that the SCD mRNA was expressed predominantly in the liver, intestine, gill, and muscle, while a lower level was found in the brain [29].

References