Lycium barbarum Polysaccharide Supplementation Improves Alcoholic Liver Injury in Female Mice by Inhibiting Stearoyl-CoA Desaturase 1.

SCOPE: Lycium barbarum polysaccharide (LBP) is a water fraction of wolfberry, which has been demonstrated to possess a hepatoprotective effect in several liver disease models. However, the anti-alcoholic liver disease (anti-ALD) mechanism of LBP has not been investigated thoroughly. Its protective effects on both male and femal mice are investigated in the current study. METHODS AND RESULTS: A chronic ethanol-fed ALD in vivo model is applied to study the effect of LBP in both male and female mice. It is observed that ethanol causes more severe liver injury in female than male mice, and the ameliorative effects of LBP are also more significant in female mice, which are impaired after complete bilateral oophorectomy. The hepatic SCD1 expression is found to be positively correlated with the severity of the liver damage and the main mediator of LBP inducer of protection. The AMPK-CPT pathway is also activated by LBP to rebalance the dysregulated lipid metabolism during ALD development. By using concurrent sodium palmitate and an ethanol-induced in vitro cell damage model in AML-12 cell line, it is characterized that LBP directly interacts with ERα instead of ERß to activate the SCD1-AMPK-CPT pathway. CONCLUSIONS: LBP is an effective and safe hepatoprotective agent against ALD primarily through the SCD1-AMPK-CPT pathway after ERα agonist.

Stearoyl-CoA desaturase 2 is required for peroxisome proliferator-activated receptor gamma expression and adipogenesis in cultured 3T3-L1 cells.

Based on recent evidence that fatty acid synthase and endogenously produced fatty acid derivatives are required for adipogenesis in 3T3-L1 adipocytes, we conducted a small interfering RNA-based screen to identify other fatty acid-metabolizing enzymes that may mediate this effect. Of 24 enzymes screened, stearoyl-CoA desaturase 2 (SCD2) was found to be uniquely and absolutely required for adipogenesis. Remarkably, SCD2 also controls the maintenance of adipocyte-specific gene expression in fully differentiated 3T3-L1 adipocytes, including the expression of SCD1. Despite the high sequence similarity between SCD2 and SCD1, silencing of SCD1 did not down-regulate 3T3-L1 cell differentiation or gene expression. SCD2 mRNA expression was also uniquely elevated 44-fold in adipose tissue upon feeding mice a high fat diet, whereas SCD1 showed little response. The inhibition of adipogenesis caused by SCD2 depletion was associated with a decrease in peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA and protein, whereas in mature adipocytes loss of SCD2 diminished PPARgamma protein levels, with little change in mRNA levels. In the latter case, SCD2 depletion did not change the degradation rate of PPARgamma protein but decreased the metabolic labeling of PPARgamma protein using [(35)S]methionine/cysteine, indicating protein translation was decreased. This requirement of SCD2 for optimal protein synthesis in fully differentiated adipocytes was verified by polysome profile analysis, where a shift in the mRNA to monosomes was apparent in response to SCD2 silencing. These results reveal that SCD2 is required for the induction and maintenance of PPARgamma protein levels and adipogenesis in 3T3-L1 cells.

Obesity and the metabolic syndrome in Mediterranean countries: a hypothesis related to olive oil.

In Mediterranean countries people would previously have consumed a diet with a high proportion of MUFA. Physical activity would have been intense with a low level of stress. The stearoyl-CoA desaturase (SCD1) system selected over thousands of years of this type of behavior must have adapted to a particular capacity of self regulation. Now, this pattern, called the "Mediterranean diet", has been broken and many people living by the Mediterranean consume a high quantity of calories, mainly from saturated or n-6-rich fats and the relative intake of MUFA has decreased. Simultaneously, physical activity has decreased and the pattern of stress has changed towards what is called a western lifestyle. In this new context, if people have a favorable, genetically conditioned SCD1 activity that will let them confront the new situation or else have some other compensatory mechanism, such as being keen on sport, etc, then they can prevent the appearance of some of the complications associated with the metabolic syndrome. If, on the other hand, the SCD1 pattern is genetically unfavorable for this new situation and they have a new cultural context, then they do not have the alternative compensatory mechanisms and the probability of developing the metabolic syndrome is high.

Trans-11-18 : 1 is effectively Delta9-desaturated compared with trans-12-18 : 1 in humans.

The aim of this human intervention study was to evaluate the Delta9-desaturation of trans-11-18 : 1 (trans-vaccenic acid; tVA) to cis-9,trans-11-18 : 2 (c9,t11 conjugated linoleic acid; CLA) and of trans-12-18 : 1 (t12) to cis-9,trans-12-18 : 2 after a short-term (7 d) and a long-term (42 d) supplementation period. The conversion rates of both trans-18 : 1 isomers were estimated by lipid analysis of serum and red blood cell membranes (RBCM). Subjects started with a 2-week adaptation period without supplements. During the 42 d intervention period, the diet of the test group was supplemented with 3 g/d of tVA and 3 g/d of t12. The diet of the control group was supplemented with a control oil. Serum tVA and t12 levels in the test group increased by fivefold and ninefold after 7 d, respectively, and by eight- and 12-fold after 42 d, respectively, when compared with the adaptation period (P< or =0.002). The serum c9,t11 CLA levels increased by 1.7- and 2.0-fold after 7 d and 42 d, respectively (P< or =0.001). After 42 d, the test group's RBCM c9,t11 CLA content was elevated by 20 % (P=0.021), whereas in the control group it was decreased by 50 % (P=0.002). The conversion rate of tVA was estimated at 24 % by serum and 19 % by RBCM. No increase in c9,t12-18 : 2 was observed in the serum and RBCM, and thus no conversion of t12 could be determined. In conclusion, the endogenous conversion of dietary tVA to c9,t11 CLA contributes approximately one quarter to the human CLA pool and should be considered when determining the CLA supply.

Loss of stearoyl-CoA desaturase expression is a frequent event in prostate carcinoma.

Prostate carcinogenesis is influenced by genetic alterations resulting in a biochemical condition that favors cell proliferation and survival. Studies of prostate carcinoma using comparative genomic hybridization and cDNA microarray analysis indicate that numerous biochemical processes may be affected during cellular transformation and progression to an invasive phenotype. Among the consistently observed tumor-associated changes are alterations in fatty acid metabolism that influence diverse cellular activities such as signaling, energy utilization, and membrane fluidity. Increases in fatty acid synthase (FAS) levels have been shown to be one of the earliest and most frequent molecular alterations in prostate carcinogenesis. We sought to identify tumor-associated changes in the expression of genes with functional roles associated with lipid metabolism. Defined populations of normal and neoplastic prostate epithelium were acquired by laser capture microdissection and transcript levels were measured by cDNA microarray hybridization. We determined that stearoyl-CoA desaturase (SCD) transcripts were downregulated in cancer relative to normal epithelium. These results were confirmed by quantitative PCR. Further analysis by immunohistochemical evaluation of radical prostatectomy samples employed a quantitative scoring system with a range of 0-300. The median SCD expression levels were 150, 45 and 10 for normal, PIN and carcinoma samples, respectively. Statistically significant differential SCD expression between normal and cancerous epithelium was determined at the p=0.001 level, and between PIN and prostate carcinoma at the p=0.03 level. Of these cases, 92% overexpressed fatty acid synthase (FAS) in cancerous cells and 84.7% exhibited the signature of FAS overexpression and SCD loss in prostate carcinoma as compared to normal prostate epithelium. These results indicate that loss of SCD expression is a frequent event in prostate adenocarcinoma, and further supports a role for altered lipid metabolism as a factor in the process of carcinogenesis.

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, a short-lived protein of endoplasmic reticulum with multiple control mechanisms.

Stearoyl-CoA desaturase (SCD) is a short-lived, polytopic membrane-bound non-heme iron enzyme localized primarily in the endoplasmic reticulum. SCD is required for the biosynthesis of monounsaturated fatty acids, and plays a key role in hepatic synthesis of triglycerides and very-low-density lipoproteins. The intracellular concentration of SCD fluctuates in a wide range in response to complex and often competing hormonal and dietary factors. A combination of transcriptional regulation and rapid protein degradation produces transient elevations of SCD enzyme activity in response to physiologic demands. Dysregulation of SCD has been implicated in non-alcoholic fatty liver disease, hyperlipidemia, and obesity.