Comprehensive analysis of stearoyl-coenzyme A desaturase in prostate adenocarcinoma: insights into gene expression, immune microenvironment and tumor progression.

Prostate adenocarcinoma (PRAD) is a prevalent global malignancy which depends more on lipid metabolism for tumor progression compared to other cancer types. Although Stearoyl-coenzyme A desaturase (SCD) is documented to regulate lipid metabolism in multiple cancers, landscape analysis of its implications in PRAD are still missing at present. Here, we conducted an analysis of diverse cancer datasets revealing elevated SCD expression in the PRAD cohort at both mRNA and protein levels. Interestingly, the elevated expression was associated with SCD promoter hypermethylation and genetic alterations, notably the L134V mutation. Integration of comprehensive tumor immunological and genomic data revealed a robust positive correlation between SCD expression levels and the abundance of CD8+ T cells and macrophages. Further analyses identified significant associations between SCD expression and various immune markers in tumor microenvironment. Single-cell transcriptomic profiling unveiled differential SCD expression patterns across distinct cell types within the prostate tumor microenvironment. The Gene Ontology and Kyoto Encyclopedia of Genes and Genome analyses showed that SCD enriched pathways were primarily related to lipid biosynthesis, cholesterol biosynthesis, endoplasmic reticulum membrane functions, and various metabolic pathways. Gene Set Enrichment Analysis highlighted the involvement of elevated SCD expression in crucial cellular processes, including the cell cycle and biosynthesis of cofactors pathways. In functional studies, SCD overexpression promoted the proliferation, metastasis and invasion of prostate cancer cells, whereas downregulation inhibits these processes. This study provides comprehensive insights into the multifaceted roles of SCD in PRAD pathogenesis, underscoring its potential as both a therapeutic target and prognostic biomarker.

Effects of CRISPR/Cas9-mediated stearoyl-Coenzyme A desaturase 1 knockout on mouse embryo development and lipid synthesis.

Background: Lipid synthesis is an indispensable process during embryo and growth development. Abnormal lipid synthesis metabolism can cause multiple metabolic diseases including obesity and hyperlipidemia. Stearoyl-Coenzyme A desaturase 1 (SCD1) is responsible for catalyzing the synthesis of monounsaturated fatty acids (MUFA) and plays an essential role in lipid metabolism. The aim of our study was to evaluate the effects of SCD1 on embryo development and lipid synthesis in a knockout mice model. Methods: We used the CRISPR/Cas9 system together with microinjection for the knockout mouse model generation. Ten-week-old female C57BL/6 mice were used for zygote collection. RNase-free water was injected into mouse zygotes at different cell phases in order to select the optimal time for microinjection. Five sgRNAs were designed and in vitro transcription was performed to obtain sgRNAs and Cas9 mRNA. RNase-free water, NC sgRNA/Cas9 mRNA, and Scd1 sgRNA/Cas9 mRNA were injected into zygotes to observe the morula and blastocyst formation rates. Embryos that were injected with Scd1 sgRNA/Cas9 mRNA and developed to the two-cell stage were used for embryo transfer. Body weight, triacylglycerol (TAG), and cholesterol in Scd1 knockout mice serum were analyzed to determine the effects of SCD1 on lipid metabolism. Results: Microinjection performed during the S phase presented with the highest zygote survival rate (P < 0.05). Of the five sgRNAs targeted to Scd1, two sgRNAs with relatively higher gene editing efficiency were used for Scd1 knockout embryos and mice generation. Genome sequence modification was observed at Scd1 exons in embryos, and Scd1 knockout reduced blastocyst formation rates (P < 0.05). Three Scd1 monoallelic knockout mice were obtained. In mice, the protein level of SCD1 decreased (P < 0.05), and the body weight and serum TAG and cholesterol contents were all reduced (P < 0.01).

DNMT3a promotes osteoblast differentiation and alleviates osteoporosis via the PPARγ/SCD1/GLUT1 axis.

Background: This study was designed to elucidate the role of DNMT3a and PPARγ functions in postmenopausal osteoporosis. Materials & methods: Mice were ovariectomized to establish an in vivo osteoporosis model and MC3T3-E1-14 osteoblasts were induced to differentiate. Gain- or loss-of-function approaches were used to manipulate the expression of PPARγ, DNMT3a and SCD1, followed by an evaluation of their role in postmenopausal osteoporosis both in vivo and in vitro. Results: DNMT3a induced methylation of the PPARγ promoter region, consequently stimulating osteoblast differentiation. PPARγ elevated SCD1, which decreased GLUT1 and inhibited osteoblast differentiation. Inhibition of PPARγ reduced SCD1 while increasing GLUT1 expression, thus alleviating postmenopausal osteoporosis in mice. Conclusion: DNMT3a promotes osteoblast differentiation and prevents postmenopausal osteoporosis by regulating the PPARγ/SCD1/GLUT1 axis.

Lipid metabolism in cancer: A systematic review.

Preclinical studies and clinical trials have emphasized the decisive role of lipid metabolism in tumor proliferation and metastasis. This systematic review aimed to explore the existing literature to evaluate the role and significance of the genes and pathways most commonly involved in the regulation of lipid metabolism in cancer. The literature search was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analyses. Approximately 2396 research articles were initially selected, of which 215 were identified as potentially relevant for abstract review. Upon further scrutiny, 62 of the 215 studies were reviews, seminars, or presentations, and 44 were original study articles and were thus included in the systematic review. The predominant gene involved in lipid metabolism in cancer was stearoyl-coenzyme A desaturase 1 (SCD1), followed by fatty acid synthase (FASN). The pathway most commonly involved in lipid metabolism in cancer was the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, followed by the mitogen activated protein kinase (MAPK) pathway. SCD1 and FASN play significant roles in the initiation and progression of cancer and represent attractive targets for potentially effective anti-cancer treatment strategies. The regulation of cancer metabolism by the Akt kinases will be an interesting topic of future study.

Glavonoid-rich oil supplementation reduces stearoyl-coenzyme A desaturase 1 expression and improves systemic metabolism in diabetic, obese KK-Ay mice.

AIMS: Glavonoid-rich oil (GRO) derived from ethanol extraction of licorice (Glycyrrhiza glabra Linne) root has been reported to have beneficial effects on health. In this study, we aimed to determine the effect of long-term administration of GRO on metabolic disorders and to elucidate the molecular mechanism. MAIN METHODS: Female obese, type 2 diabetic KK-Ay mice were fed diets supplemented with 0.3% or 0.8% GRO (w/w) for 4-12 weeks. Mice were euthanized and autopsied at 20 weeks old. The effects of GRO on lipid and glucose metabolism were evaluated by measuring physiological and biochemical markers using mRNA sequencing, quantitative reverse-transcription PCR, and western blot analyses. KEY FINDINGS: Compared to mice fed the control diet, GRO-supplemented mice had reduced body and white adipose tissue weights, serum levels of triglycerides and cholesterol, and improved glucose tolerance, while food intake was not affected. We found remarkable reductions in the gene expression levels of stearoyl-coenzyme A desaturase 1 (Scd1) and pyruvate dehydrogenase kinase isoenzyme 4 (Pdk4) in the liver, in addition to decreased expression of fatty acid synthase (Fasn) in inguinal white adipose tissue (iWAT). These results suggest that GRO supplementation improves lipid profiles via reduced de novo lipogenesis in the liver and white adipose tissue. Glucose metabolism may also be improved by increased glycolysis in the liver. SIGNIFICANCE: Our analysis of long-term supplementation of GRO in obese and diabetic mice should provide novel insight into preventing insulin resistance and metabolic syndromes.

Effect of Korean Red Ginseng on metabolic syndrome.

Metabolic syndrome (MS) refers to a clustering of at least three of the following medical conditions: high blood pressure, abdominal obesity, hyperglycemia, low high-density lipoprotein level, and high serum triglycerides. MS is related to a wide range of diseases which includes obesity, diabetes, insulin resistance, cardiovascular disease, dyslipidemia, or non-alcoholic fatty liver disease. There remains an ongoing need for improved treatment strategies for MS. The most important risk factors are dietary pattern, genetics, old age, lack of exercise, disrupted biology, medication usage, and excessive alcohol consumption, but pathophysiology of MS has not been completely identified. Korean Red Ginseng (KRG) refers to steamed/dried ginseng, traditionally associated with beneficial effects such as anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. KRG has been often used in traditional medicine to treat multiple metabolic conditions. This paper summarizes the effects of KRG in MS and related diseases such as obesity, cardiovascular disease, insulin resistance, diabetes, dyslipidemia, or non-alcoholic fatty liver disease based on experimental research and clinical studies.

MiR-1908/EXO1 and MiR-203a/FOS, regulated by scd1, are associated with fracture risk and bone health in postmenopausal diabetic women.

BACKGROUND: Stearoyl-coenzyme A desaturase-1 (SCD1) can inhibit the development of diabetic bone disease by promoting osteogenesis. In this study, we examined whether this regulation by SCD1 is achieved by regulating the expression of related miRNAs. METHODS: SCD1 expression levels were observed in human bone-marrow mesenchymal stem cells (BM-MSCs) of patients with type 2 diabetes mellitus (T2DM), and the effect of SCD1 on osteogenesis was observed in human adipose-derived MSCs transfected with the SCD1 lentiviral system. We designed a bioinformatics prediction model to select important differentially expressed miRNAs, and established protein-protein interaction and miRNA-mRNA networks. miRNAs and mRNAs were extracted and their differential expression was detected. The SCD1-miRNA-mRNA network was validated. FINDINGS: SCD1 expression in bone marrow was downregulated in patients with T2DM and low-energy fracture, and SCD1 expression promotes BM-MSC osteogenic differentiation. The predictors in the nomogram were seven microRNAs, including hsa-miR-1908 and hsa-miR-203a. SCD1 inhibited the expression of CDKN1A and FOS, but promoted the expression of EXO1 and PLS1. miR-1908 was a regulator of EXO1 expression, and miR-203a was a regulator of FOS expression. INTERPRETATION: The regulation of BM-MSCs by SCD1 is a necessary condition for osteogenesis through the miR-203a/FOS and miR-1908/EXO1 regulatory pathways.

SCD1 activity promotes cell migration via a PLD-mTOR pathway in the MDA-MB-231 triple-negative breast cancer cell line.

BACKGROUND: Breast cancer is the most common cancer in women. Despite high survival rates in Western countries, treatments are less effective in metastatic cases and triple-negative breast cancer (TNBC) patient survival is the shortest across breast cancer subtypes. High expression levels of stearoyl-CoA desaturase-1 (SCD1) have been reported in breast cancer. The SCD1 enzyme catalyzes the formation of oleic acid (OA), a lipid stimulating the migration of metastatic breast cancer cells. Phospholipase activity is also implicated in breast cancer metastasis, notably phospholipase D (PLD). METHODS: Kaplan-Meier survival plots generated from gene expression databases were used to analyze the involvement of SCD1 and PLD in several cancer subtypes. SCD1 enzymatic activity was modulated with a pharmaceutical inhibitor or by OA treatment (to mimic SCD1 over-activity) in three breast cancer cell lines: TNBC-derived MDA-MB-231 cells as well as non-TNBC MCF-7 and T47D cells. Cell morphology and migration properties were characterized by various complementary methods. RESULTS: Our survival analyses suggest that SCD1 and PLD2 expression in the primary tumor are both associated to metastasis-related morbid outcomes in breast cancer patients. We show that modulation of SCD1 activity is associated with the modification of TNBC cell migration properties, including changes in speed, direction and cell morphology. Cell migration properties are regulated by SCD1 activity through a PLD-mTOR/p70S6K signaling pathway. These effects are not observed in non-TNBC cell lines. CONCLUSION: Our results establish a key role for the lipid desaturase SCD1 and delineate an OA-PLD-mTOR/p70S6K signaling pathway in TNBC-derived MDA-MB-231 cell migration.

Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II.

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.

Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway.

Non-alcoholic steatohepatitis (NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57BL/6 mice fed with methionine- choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h, then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibinin significantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2E1 and CYP4A in vivo. These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the ß-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity (CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity (CYP2E1 and CYP4A) to relieve oxidative stress.

Identification and characterization of stearoyl-CoA desaturase in Toxoplasma gondii.

Few information of the function of stearoyl-coenzyme A (CoA) desaturase (SCD) in apicomplaxan parasite has been obtained. In this study, we retrieved a putative fatty acyl-CoA desaturase (TGGT1_238950) by a protein alignment with Plasmodium falciparum SCD in ToxoDB. A typical Δ9-desaturase domain was revealed in this protein. The putative desaturase was tagged with HA endogenously in Toxoplasma gondii, and the endoplasmic reticulum localization of the putative desaturase was revealed, which was consistent with the fatty acid desaturases in other organisms. Therefore, the TGGT1_238950 was designated T. gondii SCD. Based on CRISPR/Cas9 gene editing technology, SCD conditional knockout mutants in the T. gondii TATi strain were obtained. The growth in vitro and pathogenicity in mice of the mutants suggested that SCD might be dispensable for tachyzoite growth and proliferation. The SCD-overexpressing line was constructed to further explore SCD function. The portion of palmitoleic acid and oleic acid were increased in SCD-overexpressing parasites, compared with the RH parental strain, indicating that T. gondii indeed is competent for unsaturated fatty acid synthesis. The SCD-overexpressing tachyzoites propagated slower than the parental strain, with a decreased invasion capability and weaker pathogenicity in mice. The TgIF2α phosphorylation and the expression changes of several genes demonstrated that ER stress was triggered in the SCD-overexpressing parasites, which were more apt toward autophagy and apoptosis. The function of unsaturated fatty acid synthesis of TgSCD was consistent with our hypothesis. On the other hand, SCD might also be involved in tachyzoite autophagy and apoptosis.

SCD1 methylation in subcutaneous adipose tissue associated with menopausal age.

Objective: This study was designed to investigate associations between menopausal age and the DNA methylation levels of stearoyl-coenzyme A desaturase 1 (SCD1, selected by the Illumina Human Methylation 450 K Bead Chip) and explore the changes in mRNA levels of SCD1 and DNA methyltransferases (DNMTs) in response to estrogen replacement therapy (ERT). Methods: In the human experiment, we performed subcutaneous adipose tissue DNA extraction on 85 menopausal women. Methylation of SCD1 was measured by MethyLight polymerase chain reaction. In the rat experiment, we established models of menopause (ovariectomy group) and ERT (ovariectomy + 17ß-estradiol group). The mRNA levels of SCD1, DNMT1, DNMT3A, and DNMT3B were determined. Results: The results showed that DNA methylation of SCD1 was inversely correlated with menopausal age (r = 0.370, P < 0.001). In the rat study, the mRNA levels of SCD1 decreased (P < 0.001) and those of DNMT3A (P < 0.001) and DNMT3B increased (P < 0.001) after ERT. Conclusion: Methylation levels of SCD1 were significantly associated with menopausal age. DNMT3A and DNMT3B may be involved in the methylation of SCD1.

Isolated hypercholesterolemia leads to steatosis in the liver without affecting the pancreas.

BACKGROUND: Lipid accumulation in the liver and pancreas is primarily caused by combined hyperlipidemia. However, the effect of isolated hypercholesterolemia without hypertriglyceridemia is not fully described. Therefore, our aim was to investigate whether hypercholesterolemia alone leads to alterations both in hepatic and pancreatic lipid panel and histology in rats. METHODS: Male Wistar rats were fed with 2% cholesterol +0.25% cholate-supplemented diet or standard chow for 12 weeks. Blood was collected at weeks 0, 4, 8 and 12 to measure serum cholesterol and triglyceride levels. At week 12, both the pancreas and the liver were isolated for further histological and biochemical analysis. Hepatic and plasma fatty acid composition was assessed by gas chromatography. Expression of mRNA of major enzymes involved in saturated/unsaturated fatty acid synthesis was analyzed by qPCR. In separate experiments serum enzyme activities and insulin levels were measured at week 9. RESULTS: At week 12, rats fed with 2% cholesterol +0.25% cholate-supplemented diet were characterized by elevated serum cholesterol (4.09 ± 0.20 vs. 2.89 ± 0.22 mmol/L, *p < 0.05) while triglyceride (2.27 ± 0.05 vs. 2.03 ± 0.03 mmol/L) and glucose levels (5.32 ± 0.14 vs. 5.23 ± 0.10 mmol/L) remained unchanged. Isolated hypercholesterolemia increased hepatic lipid accumulation, hepatic cholesterol (5.86 ± 0.22 vs. 1.60 ± 0.15 ng/g tissue, *p < 0.05) and triglyceride contents (19.28 ± 1.42 vs. 6.78 ± 0.71 ng/g tissue, *p < 0.05), and hepatic nitrotyrosine level (4.07 ± 0.52 vs. 2.59 ± 0.31 ng/mg protein, *p < 0.05). The histology and tissue lipid content of the pancreas was not affected. Serum total protein level, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities remained unchanged in response to isolated hypercholesterolemia while serum alkaline phosphatase activity (ALP) significantly increased. Plasma insulin levels did not change in response to isolated hypercholesterolemia suggesting an intact endocrine function of the pancreas. Isolated hypercholesterolemia caused a significantly increased hepatic and serum fatty acid level associated with a marked alteration of fatty acid composition. Hepatic expression of Δ9-desaturase (SCD1) was increased 4.92×, while expression of Δ5-desaturase and Δ6-desaturase were decreased (0.447× and 0.577×, respectively) due to isolated hypercholesterolemia. CONCLUSIONS: Isolated hypercholesterolemia leads to hepatic steatosis and marked alterations in the hepatic lipid profile without affecting the pancreas. Altered fatty acid profile might mediate harmful effects of cholesterol in the liver.

Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents.

A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.

Carcass and Meat Characteristics and Gene Expression in Intramuscular Adipose Tissue of Korean Native Cattle Fed Finishing Diets Supplemented with 5% Palm Oil.

We hypothesized that supplementing finishing diets with palm oil would promote adipogenic gene expression but depress stearoyl-CoA desaturase (SCD) gene expression in intramuscular (i.m.) adipose tissues of Hanwoo steers during fattening period (from 16 to 32 mon of age). Fourteen Hanwoo steers were allotted randomly to 2 groups of 7 steers based on initial BW and fed either a basal diet (control) or the basal diet supplemented with 5% palm oil (BDSP). At slaughter, i.m. adipose tissue was harvested for analysis of adipogenic gene expression and fatty acid composition. There were no differences in BW or average daily gain between treatment groups. Supplemental palm oil had no effect on carcass quality traits (carcass weight, backfat thickness, loin muscle area, or marbling scores) or meat color values. Palm oil increased (p<0.05) expression of AMP-activated protein kinase-α and peroxisome proliferator-activated receptor-γ, but decreased (p<0.05) CAAT/enhancer binding protein-ß gene expression and tended to decrease stearoyl-CoA desaturase gene expression in i.m. adipose tissue. Palm oil increased total i.m. polyunsaturated fatty acids (p<0.05) compared to the control i.m. adipose tissue, but had no effect on saturated or monounsaturated fatty acids. Although there were significant effects of supplemental palm oil on i.m. adipose tissue gene expression, the absence of negative effects on carcass and meat characteristics indicates that palm oil could be a suitable dietary supplement for the production of Hanwoo beef cattle.

Altered fatty acid metabolism and reduced stearoyl-coenzyme a desaturase activity in asthma.

BACKGROUND: Fatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models. METHODS: Medium- and long-chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl-coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity. RESULTS: The serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper-responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL-4 and IL-13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus-induced IP-10 secretion, which was associated with increased viral titers. CONCLUSIONS: This is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper-responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients.

Reduction in liver fat by dietary MUFA in type 2 diabetes is helped by enhanced hepatic fat oxidation.

AIMS/HYPOTHESIS: The aim of this work was to investigate hepatic lipid metabolic processes possibly involved in the reduction of liver fat content (LF) observed in patients with type 2 diabetes after an isoenergetic diet enriched in monounsaturated fatty acids (MUFAs). METHODS: This is an ancillary analysis of a published study. In a parallel-group design, 30 men and eight women, aged 35-70 years, with type 2 diabetes and whose blood glucose was controlled satisfactorily (HbA1c < 7.5% [58 mmol/mol]) by diet or diet plus metformin, were randomised by MINIM software to follow either a high-carbohydrate/high-fibre/low-glycaemic index diet (CHO/fibre diet, n = 20) or a high-MUFA diet (MUFA diet, n = 18) for 8 weeks. The assigned diets were known for the participants and blinded for people doing measurements. Before and after intervention, LF was measured by 1H-MRS (primary outcome) and indirect indices of de novo lipogenesis (DNL) (serum triacylglycerol palmitic:linoleic acid ratio), stearoyl-CoA desaturase activity (SCD-1) (serum triacylglycerol palmitoleic:palmitic acid ratio) and hepatic ß-oxidation of fatty acids (ß-hydroxybutyrate plasma concentrations) were measured. RESULTS: LF was reduced by 30% after the MUFA diet, as already reported. Postprandial ß-hydroxybutyrate incremental AUC (iAUC) was significantly less suppressed after the MUFA diet (n = 16) (-2504 ± 4488 µmol/l × 360 min vs baseline -9021 ± 6489 µmol/l × 360 min) while it was unchanged after the CHO/fibre diet (n = 17) (-8168 ± 9827 µmol/l × 360 min vs baseline -7206 ± 10,005 µmol/l × 360 min, p = 0.962) (mean ± SD, p = 0.043). In the participants assigned to the MUFA diet, the change in postprandial ß-hydroxybutyrate iAUC was inversely associated with the change in LF (r = -0.642, p = 0.010). DNL and SCD-1 indirect indices did not change significantly after either of the dietary interventions. CONCLUSIONS/INTERPRETATION: Postprandial hepatic oxidation of fatty acids is a metabolic process possibly involved in the reduction of LF by a MUFA-rich diet in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01025856 FUNDING : The study was funded by Ministero Istruzione Università e Ricerca and Italian Minister of Health.

The Expression of Adipogenic Genes in Adipose Tissues of Feedlot Steers Fed Supplementary Palm Oil or Soybean Oil.

We hypothesized that supplementing finishing diets with palm oil would promote adipogenic gene expression and stearoyl-CoA desaturase (SCD) gene expression in subcutaneous (s.c.) and intramuscular (i.m.) adipose tissues of feedlot steers. Eighteen Angus and Angus crossbred steers were assigned to three groups of 6 steers and fed a basal diet (control), with 3% palm oil, or with 3% soybean oil, for 70 d, top-dressed daily. Tailhead s.c. adipose tissue was obtained by biopsy at 14 d before the initiation of dietary treatments and at 35 d of dietary treatments. At slaughter, after 70 d of dietary treatment, tailhead s.c. adipose tissue and i.m. adipose tissue were obtained from the longissimus thoracis muscle. Palm oil increased plasma palmitic acid and soybean oil increased plasma linoleic acid and α-linolenic acid relative to the initial sampling time. Expression of AMP-activated protein kinase alpha (AMPKα) and peroxisome proliferator-activated receptor gamma (PPARγ) increased between the initial and intermediate biopsies and declined thereafter (p<0.03). SCD gene expression did not change between the initial and intermediate biopsies but declined by over 75% by the final period (p = 0.04), and G-coupled protein receptor 43 (GPR43) gene expression was unaffected by diet or time on trial. Soybean oil decreased (p = 0.01) PPARγ gene expression at the intermediate sample time. At the terminal sample time, PPARγ and SCD gene expression was less in i.m. adipose tissue than in s.c. adipose tissue (p<0.05). AMPKα gene expression was less in s.c. adipose tissue of palm oil-fed steers than in control steers (p = 0.04) and CCAAT enhancer binding protein-beta (CEBPß) gene expression was less in s.c. and i.m. adipose tissues of palm oil-fed steers than in soybean oil-fed steers (p<0.03). Soybean oil decreased SCD gene expression in s.c. adipose tissue (p = 0.05); SCD gene expression in palm oil-fed steers was intermediate between control and soybean oil-fed steers. Contrary to our original hypothesis, palm oil did not promote adipogenic gene expression in s.c. and i.m. adipose tissue.

The role of stearoyl-coenzyme A desaturase 1 in clear cell renal cell carcinoma.

This study aimed to investigate the correlations of stearoyl-coenzyme A desaturase 1 (SCD-1) with clear cell renal cell carcinoma (ccRCC) severity and PI3K-AKT-mTOR signaling pathway. From 2004 to 2006, tumor tissue and normal pericarcinomatous tissue from ccRCC samples were collected from ccRCC patients at Renji Hospital of Shanghai Jiaotong University. The expression of SCD-1 in the collected ccRCC samples and four cell lines (A498, 769-P, 786-O, and CAKI) was detected by Western blot. The correlation between SCD-1 expression and ccRCC severity was also analyzed by immunohistochemistry. Stable 786-O and 769-P ccRCC cells expressing SCD-1 short hairpin RNA (shRNA) were constructed, and the expression of proteins in the PI3K-AKT-mTOR signaling pathway was also detected. Finally, the inhibitory effect of PI3K-AKT-mTOR inhibitors (PI103, MK2206, rapamycin, AZD8055, and RAD001) on ccRCC cells stably expressing SCD-1 shRNA was also measured. Higher SCD-1 expression level was observed in ccRCC tissues compared with normal tissues. SCD-1 expression level was the highest in 786-O. SCD-1 expression was positively correlated with the tumor-node-metastasis (TNM) stage, grade of tumor cells, and lymphatic metastasis. There were no changes in the expression of AKT, ERK, PI3K, and PDK1. Significant differences were observed in the expression of p-AKT (at the Ser473 and Thr308 site), p-ERK, and two mTOR downstream molecules (4E-BP1 and p-P70S6K1) in cells stably expressing SCD-1 shRNA. PI103 and AZD8055 could enhance the inhibitory effect of SCD-1 interference on proliferation and migration of 786-O and 769-P cells. AZD8055 is recommended for the combined ccRCC treatment with shRNA interference.