硬脂酰辅酶A去饱和酶与脂代谢调控

硬脂酰辅酶A去饱和酶（stearoyl-coenzyme A desaturase,SCD）是催化饱和脂酰辅酶A生成单不饱和脂酰辅酶A的关键酶,在不同的组织中有多种亚型分布。高热量饮食、运动、激素等因素均影响SCD的基因表达水平。对SCD蛋白表达水平和活性的调控会直接影响生物体内饱和脂肪酸（saturated fatty acid,SFA）与单不饱和脂肪酸（monounsaturated fatty acid,MUFA）的比例,从而进一步影响整个机体的脂质代谢,进而与细胞应激反应及胰岛素敏感性直接相关。因此,SCD逐渐成为代谢疾病治疗的一个潜在的靶分子。     

Recent insights into stearoyl-CoA desaturase-1

PURPOSE OF REVIEW: Stearoyl-Coenzyme A (CoA) desaturase is a central lipogenic enzyme catalyzing the synthesis of monounsaturated fatty acids - mainly oleate (C(18:1)). Oleate is the most abundant monounsaturated fatty acid in dietary fat and is therefore readily available. Why, then, is stearoyl-CoA desaturase a highly regulated enzyme? This review summarizes the recent and timely advances concerning the important role of stearoyl-CoA desaturase in metabolism. RECENT FINDINGS: Recent findings using mice that have a naturally occurring mutation in the SCD1 gene isoform as well as a mouse model with a targeted disruption of the stearoyl-CoA desaturase gene-1 (SCD1-/-) have revealed the role of de-novo synthesized oleate and thus the physiological importance of SCD1 expression. In the highlighted references, it is shown that the SCD1-/- mice have reduced body adiposity, increased insulin sensitivity, and are resistant to diet-induced obesity. The expression of several genes of lipid oxidation is upregulated, whereas lipid synthesis genes are downregulated. SCD1 was also found to be a component of the novel metabolic response to the hormone leptin. SUMMARY: SCD1, therefore, appears to be an important metabolic control point, and inhibition of its expression could be of benefit for the treatment of obesity, diabetes and other metabolic diseases.     

Systemic Down-Regulation of Delta-9 Desaturase Promotes Muscle Oxidative Metabolism and Accelerates Muscle Function Recovery following Nerve Injury

The progressive deterioration of the neuromuscular axis is typically observed in degenerative conditions of the lower motor neurons, such as amyotrophic lateral sclerosis (ALS). Neurodegeneration in this disease is associated with systemic metabolic perturbations, including hypermetabolism and dyslipidemia. Our previous gene profiling studies on ALS muscle revealed down-regulation of delta-9 desaturase, or SCD1, which is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Interestingly, knocking out SCD1 gene is known to induce hypermetabolism and stimulate fatty acid beta-oxidation. Here we investigated whether SCD1 deficiency can affect muscle function and its restoration in response to injury. The genetic ablation of SCD1 was not detrimental per se to muscle function. On the contrary, muscles in SCD1 knockout mice shifted toward a more oxidative metabolism, and enhanced the expression of synaptic genes. Repressing SCD1 expression or reducing SCD-dependent enzymatic activity accelerated the recovery of muscle function after inducing sciatic nerve crush. Overall, these findings provide evidence for a new role of SCD1 in modulating the restorative potential of skeletal muscles.     

Lack of stearoyl-CoA desaturase 1 upregulates basal thermogenesis but causes hypothermia in a cold environment

Stearoyl-CoA desaturase (SCD) is a microsomal enzyme involved in the biosynthesis of oleate and palmitoleate. Mice with a targeted disruption of the SCD1 isoform (SCD1-/-) exhibit reduced adiposity and increased energy expenditure. To address whether the energy expenditure is attributable to increased thermogenesis, we investigated the effect of SCD1 deficiency on basal and cold-induced thermogenesis. SCD1-/- mice have increased expression of uncoupling proteins in brown adipose tissue (BAT) relative to controls. The beta3-adrenergic receptor (beta3-AR) expression was increased and the phosphorylation of cAMP response element binding protein and the protein level of peroxisome proliferator-activated receptor-gamma coactivator-1alpha were increased in the SCD1-/- mice. Both lipolysis and fatty acid oxidation were increased in the SCD1-/- mice. When exposed to 4 degrees C, SCD1-/- mice showed hypothermia, hypoglycemia, and depleted liver glycogen. High levels of dietary oleate partially compensated for the hypothermia and rescued plasma glucose and liver glycogen. These results suggest that SCD1 deficiency stimulates basal thermogenesis through the upregulation of the beta3-AR-mediated pathway and a subsequent increase in lipolysis and fatty acid oxidation in BAT. The hypothermia and hypoglycemia in cold-exposed SCD1-/- mice and the compensatory recovery by oleate indicate an important role of SCD1 gene expression in thermoregulation.     

Transforming growth factor-beta regulates stearoyl coenzyme A desaturase expression through a Smad signaling pathway.

The regulation of stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the synthesis of unsaturated fatty acids, is physiologically important because the ratio of saturated to unsaturated fatty acids is thought to control cellular functions by modulating the structural integrity and fluidity of cell membranes. Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, increased SCD mRNA expression in cultured human retinal pigment epithelial cells. This response was elicited by all three TGF-beta isoforms, beta1, beta2, and beta3. However, SCD mRNA expression was not increased either by other members of the TGF-beta family or by other growth factors or cytokines. TGF-beta also increased SCD mRNA expression in several other cell lines tested. The increase in SCD mRNA expression was preceded by a marked increase in Smad2 phosphorylation in TGF-beta-treated human retinal pigment epithelial cells. TGF-beta did not induce SCD mRNA expression in a Smad4-deficient cell line. However, Smad4 overexpression restored the TGF-beta effect in this cell line. Moreover, TGF-beta-induced SCD mRNA expression was effectively blocked by the overexpression of Smad7, an inhibitory Smad. Thus, a TGF-beta signal transduction pathway involving Smad proteins appears to regulate the cellular expression of the SCD gene, and this regulation may play an important role in lipid metabolism.     

Stearoyl-CoA desaturase-1 (SCD1) augments saturated fatty acid-induced lipid accumulation and inhibits apoptosis in cardiac myocytes

Mismatch between the uptake and utilization of long-chain fatty acids in the myocardium leads to abnormally high intracellular fatty acid concentration, which ultimately induces myocardial dysfunction. Stearoyl-Coenzyme A desaturase-1 (SCD1) is a rate-limiting enzyme that converts saturated fatty acids (SFAs) to monounsaturated fatty acids. Previous studies have shown that SCD1-deficinent mice are protected from insulin resistance and diet-induced obesity; however, the role of SCD1 in the heart remains to be determined. We examined the expression of SCD1 in obese rat hearts induced by a sucrose-rich diet for 3 months. We also examined the effect of SCD1 on myocardial energy metabolism and apoptotic cell death in neonatal rat cardiac myocytes in the presence of SFAs. Here we showed that the expression of SCD1 increases 3.6-fold without measurable change in the expression of lipogenic genes in the heart of rats fed a high-sucrose diet. Forced SCD1 expression augmented palmitic acid-induced lipid accumulation, but attenuated excess fatty acid oxidation and restored reduced glucose oxidation. Of importance, SCD1 substantially inhibited SFA-induced caspase 3 activation, ceramide synthesis, diacylglycerol synthesis, apoptotic cell death, and mitochondrial reactive oxygen species (ROS) generation. Experiments using SCD1 siRNA confirmed these observations. Furthermore, we showed that exposure of cardiac myocytes to glucose and insulin induced SCD1 expression. Our results indicate that SCD1 is highly regulated by a metabolic syndrome component in the heart, and such induction of SCD1 serves to alleviate SFA-induced adverse fatty acid catabolism, and eventually to prevent SFAs-induced apoptosis.     

Regulation of stearoyl-CoA desaturase genes: role in cellular metabolism and preadipocyte differentiation

The degree of fatty acid unsaturation in cell membrane lipids determines membrane fluidity, whose alteration has been implicated in a variety of disease states including diabetes, obesity, hypertension, cancer, and neurological and heart diseases. Stearoyl-CoA desaturase (SCD) is a key rate-limiting enzyme in the synthesis of unsaturated fatty acids by insertion of a cis-double bond in the Delta9 position of fatty acid substrates. Palmitate and stearate are the preferred substrates, which are converted to palmitoleate and oleate, respectively. These monounsaturated fatty acids are the major constituents of cellular membrane phospholipids and triacylglycerol stores found in adipose tissue. Two mouse and rat SCD genes (SCD1 and SCD2) have been cloned and characterized. During the differentiation of 3T3-L1 preadipocytes into adipocytes, SCD1 and SCD2 mRNAs are induced concomitant with increased de novo synthesis of palmitoleate and oleate. The physiological significance of expressing the two isoforms in the adipocytes is currently unknown. In this review we discuss the role of the SCD isoforms in metabolism and the recent findings on the differential regulation of mouse SCD genes by the antidiabetic thiazolidinediones (TZDs), during preadipocyte differentiation.     

Modulation of SCD1 activity in hepatocyte cell lines: evaluation of genomic stability and proliferation

Molecular and Cellular Biochemistry - Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme for the synthesis of monounsaturated fatty acids (MUFA). SCD1 overexpression is associated with a...     

Regulation of stearoyl-CoA desaturases and role in metabolism

Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (18:1) and palmitoleate (16:1). These represent the major monounsaturated fatty acids of membrane phospholipids, triglycerides, wax esters and cholesterol esters. The ratio of saturated to monounsaturated fatty acids affects phospholipid composition and alteration in this ratio has been implicated in a variety of disease states including cardiovascular disease, obesity, diabetes, neurological disease, and cancer. For this reason, the expression of SCD is of physiological significance in both normal and disease states. Several SCD gene isoforms (SCD1, SCD2, SCD3) exist in the mouse and one SCD isoform that is highly homologous to the mouse SCD1 is well characterized in human. The physiological role of each SCD isoform and the reason for having three or more SCD gene isoforms in the rodent genome are currently unknown but could be related the substrate specificities of the isomers and their regulation through tissue-specific expression. The recent studies of asebia mouse strains that have a natural mutation in the SCD1 gene and a mouse model with a targeted disruption of the SCD1 gene have provided clues concerning the role that SCD1 and its endogenous products play in the regulation of metabolism.     

SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway.     

Stearoyl-CoA desaturase and insulin signaling — What is the molecular switch?

Increasing evidence suggests that stearoyl-CoA desaturase (SCD), the rate-limiting enzyme of monounsaturated fatty acid biosynthesis, is an important factor in the pathogenesis of lipid-induced insulin resistance. Mice with a targeted disruption of the SCD1 gene have improved glucose tolerance compared to wild-type mice, despite lower fasting plasma insulin levels. Increased SCD activity has been found in insulin-resistant humans and animals, whereas SCD1 deficiency attenuates both diet- and genetically-induced impairment of insulin action. Phosphorylation of serine and threonine residues on insulin receptor, insulin receptor substrates (IRS1 and IRS2), and on Akt has been shown to be the major step in insulin signaling that is altered due to the lack of SCD1. In this review we discuss perturbations in cell signaling and lipid metabolism cascades in insulin-sensitive tissues due to SCD1 deficiency. In particular, we address the role of cellular signaling molecules including free fatty acids, ceramides, fatty acyl-CoAs, AMP-activated protein kinase, protein tyrosine phosphatase 1B as well as of membrane fluidity. While the precise mechanism of SCD action on insulin signaling remains to be clarified, current findings on SCD point to a very promising novel target for the treatment of insulin resistance.     

Identification and characterization of murine SCD4, a novel heart-specific stearoyl-CoA desaturase isoform regulated by leptin and dietary factors

Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. Thus far, three isoforms of SCD (SCD1, SCD2, and SCD3) have been identified and characterized. Regulation of the SCD1 isoform has been shown to be an important component of the metabolic actions of leptin in liver, but the effects of leptin on SCD isoforms in other tissues have not been investigated. We found that although the mRNA levels of SCD1 and SCD2 were not affected by leptin deficiency in the hearts of ob/ob mice, the SCD activity and levels of monounsaturated fatty acids were increased, implying the existence of another SCD isoform. This observation has led to the cDNA cloning and characterization of a fourth SCD isoform (SCD4) that is expressed exclusively in the heart. SCD4 encodes a 352-amino acid protein that shares 79% sequence identity with the SCD1, SCD2, and SCD3 isoforms. Liver X receptor alpha (LXR alpha) agonists and a high carbohydrate fat-free diet induced SCD4 expression, but unlike SCD1, SCD4 expression was not repressed by dietary polyunsaturated fatty acids. SCD4 mRNA levels were elevated 5-fold in the hearts of leptin-deficient ob/ob mice relative to wild type controls. Treatment of ob/ob mice with leptin decreased mRNA levels of SCD4, whereas levels of SCD1 and SCD2 were not affected. Furthermore, in the hearts of SCD1-deficient mice, SCD4 mRNA levels were induced 3-fold, whereas the levels of SCD2 were not altered. The current studies identify a novel heart-specific SCD isoform that demonstrates tissue-specific regulation by leptin and dietary factors.     

Stearoyl-CoA desaturase enzyme 1 inhibition reduces glucose utilization for de novo fatty acid synthesis and cell proliferation in 3T3-L1 adipocytes

Stearoyl-CoA desaturase enzyme 1 (SCD1) is a lipogenic enzyme that is upregulated in obesity, insulin resistance, and cancer. Since glucose is a substrate for both de novo fatty acid synthesis and deoxyribose synthesis, we hypothesized that SCD1 affects these multiple synthetic pathways through changes in glucose utilization. This study determined glucose utilization for fatty acid synthesis and cell proliferation in 3T3-L1 preadipocytes during SCD1 inhibition. The effects of SCD1 on cellular metabolism as mediated by its monounstaurated fatty acid products (palmitoleate and oleate) were also observed. 3T3-L1 preadipocytes underwent differentiation induction in conjunction with one of the following treatments for 4 days: (A) no treatment, (B) SCD1 inhibitor CGX0290, (C) CGX0290 + palmitoleate, or (D) CGX0290 + oleate. All cells received medium with 50 % [U¹³C]-glucose. Cells were harvested on day 7 for studies of fatty acid metabolism, tricarboxylic acid (TCA) cycle activities, and deoxyribose synthesis. CGX0290 decreased fatty acid desaturation, glucose utilization for fatty acid synthesis (acetyl-CoA enrichment), and de novo synthesis. CGX0290 treatment also led to decreased cell density through increased cell death. Further analysis showed that deoxyribose new synthesis and oxidative pentose phosphate pathway activity were unchanged, while non-oxidative transketolase pathway activity was stimulated. Palmitoleate and oleate supplementation each partially ameliorated the effects of CGX0290. In 3T3-L1 cells, SCD1 promotes glucose utilization for fatty acid synthesis. In cell proliferation, SCD1 may promote cell survival, but does not impact the oxidative pathway of deoxyribose production. These effects may be mediated through the production of palmitoleate and oleate.     

Correlation of the fatty acid composition and fluid property of the cholesteryl esters in the serum of Nigerian children with sickle cell disease and healthy controls

In a previous study conducted in Nigeria, we found that children with sickle cell disease (SCD) had exceedingly low total serum cholesterol levels (mean=100-102mg/dl). The fact that significant reductions in the levels of certain polyunsaturated fatty acids (PUFA) have been documented in the serum phospholipids of these same SCD subjects led us to inquire as to the fatty acid composition of the cholesteryl esters (CE) in their serum. Lecithin:cholesterol acyl transferase (LCAT), the enzyme in blood that catalyzes the reaction in which tissue cholesterol is acylated prior to its removal from cell membranes, is relatively specific for certain PUFA. CE in blood serum from 43 male and 42 female children with SCD, ages 4-18 years, and equal numbers of age- and gender-matched controls were analyzed for their fatty acid composition. Relative to the non-SCD controls, the CE of the SCD subjects contained 9% less linoleic acid, 16% less arachidonic acid, 40% less alpha-linolenic acid, 50% less eicosapentaenoic acid, and 36% less docosahexaenoic acid, but 15% more palmitic acid and 10% more oleic acid. Overall, the acyl chains of the CE of the SCD subjects were less fluid than those of the controls, as determined by comparison of their mean melting points (MMP) and double bond indices (DBI). MMP and DBI were both estimated from the individual constituent fatty acids comprising the CE acyl chains. The strongest correlations between MMP and fatty acid mole percent were seen with palmitic acid and linoleic acid. These results show that the fatty acid composition of the serum CE of children with SCD is abnormal relative to controls who do not have this hematologic disorder. We speculate that suboptimal fatty acid nutrition in Nigerian children with SCD compromises their ability to remove cholesterol from their tissues due to preference of the LCAT enzyme for PUFA, thereby accounting, in part at least, for the low total serum cholesterol levels one finds in children with SCD.     

Lack of stearoyl-CoA desaturase-1 function induces a palmitoyl-CoA Delta6 desaturase and represses the stearoyl-CoA desaturase-3 gene in the preputial glands of the mouse

The mouse preputial gland (PG), a specialized sebaceous structure, is rich in wax esters, triglycerides, and alkyl-2,3-diacylglycerol. We have found that the mouse PG expresses the three gene isoforms (SCD1, SCD2, and SCD3) of the Delta9 stearoyl-CoA desaturase enzyme that catalyzes the biosynthesis of monounsaturated fatty acids mainly, C16:1n-7 and C18:1n-9. However, mice with a targeted disruption in the SCD1 isoform (SCD1(-/-)) have undetectable SCD3 mRNA expression in the PG while the expression of SCD2 isoform was not altered. The levels of C16:1n-7 were reduced by greater than 70% while that of C18:1n-9 were reduced by 28%. The content of the C16:1n-10 (Delta6 hexadecenoic acid) isomer and a major fatty acid of the PG was increased by greater than 2-fold, mainly in the wax ester fraction of the SCD1(-/-) mouse. We demonstrate that the increase in C16:1n-10 is due to induction of a specific palmitoyl-CoA Delta6 desaturase activity. Testosterone administration to the SCD1(-/-) mouse induced SCD3 mRNA expression and resulted in an increase in the Delta9 desaturation of 16:0-CoA, but not of 18:0-CoA. These observations demonstrate that loss of SCD1 function alters the expression of SCD3 and reveal for the first time the presence and regulation of a palmitoyl-CoA Delta6 desaturase enzyme in mammals.     

Role of stearoyl-coenzyme A desaturase in lipid metabolism

Stearoyl-CoA desaturase (SCD) (EC 1.14.99.5) is an endoplasmic reticulum-bound enzyme that catalyzes the delta9-cis desaturation of saturated fatty acyl-CoAs, the preferred substrates being palmitoyl- and stearoyl-CoA, which are converted to palmitoleoyl- and oleoyl-CoA, respectively. These monounsaturated fatty acids are used as substrates for the synthesis of triglycerides, wax esters, cholesteryl esters and membrane phospholipids. The saturated to monounsaturated fatty acid ratio affects membrane phospholipid composition and alteration in this ratio has been implicated in a variety of disease states including cardiovascular disease, obesity, diabetes, neurological disease, skin disorders and cancer. Thus, the expression of SCD is of physiological importance in normal and disease states. Several mammalian SCD genes have been cloned. A single human, three mouse and two rat are the best characterized SCD genes. The physiological role of each SCD isoform and the reason for having three or more SCD gene isoforms in the rodent genome are currently unknown. A clue as to the physiological role of the SCD, at least SCD1 gene and its endogenous products came from recent studies of asebia mouse strains that have a natural mutation in the SCD1 gene and a mouse model with a targeted disruption of the SCD1 gene. In this review we discuss our current understanding of the physiological role of SCD in lipid synthesis and metabolism.