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Osteoporosis is a common skeletal disease, primarily associated with aging, that results from decreased bone density and bone volume. This reduction significantly increases the risk of fractures in osteoporosis patients compared to individuals with normal bone density. Additionally, the bone regeneration process in these patients is slow, making complete healing difficult. Along with the decline in bone volume and density, osteoporosis is characterized by an increase in marrow adipose tissue (MAT), which is fat within the bone. In this altered bone microenvironment, osteoblasts are influenced by various factors secreted by adipocytes. Notably, saturated fatty acids promote osteoclast activity, inhibit osteoblast differentiation, and induce apoptosis, further reducing osteoblast formation. In contrast, monounsaturated fatty acids inhibit osteoclast formation and mitigate the apoptosis caused by saturated fatty acids. Leveraging these properties, we aimed to investigate the effects of overexpressing stearoyl-CoA desaturase 1 (SCD1), an enzyme that converts saturated fatty acids into monounsaturated fatty acids, on osteogenic differentiation and bone regeneration in both in vivo and in vitro models. Through this novel approach, we seek to develop a stem cell-based therapeutic strategy that harnesses SCD1 to improve bone regeneration in the adipocyte-rich osteoporotic environment.

Background: Cancer cells exhibit remarkable metabolic plasticity, enabling them to adapt to fluctuating nutrient conditions. This study investigates the impact of a combination of low glucose levels and inhibition of stearoyl-CoA desaturase 1 (SCD1) using A939572 on cancer metabolic plasticity and growth., Methods: A comprehensive metabolomic and lipidomic analysis was conducted to unravel the intricate changes in cellular metabolites and lipids. MCF-7 cells were subjected to low glucose conditions, and SCD1 was inhibited using A939572. The resulting alterations in metabolic pathways and lipid profiles were explored to elucidate the synergistic effects on cancer cell physiology., Results: The combination of low glucose and A939572-induced SCD1 inhibition significantly impaired cancer cell metabolic plasticity. Metabolomic analysis highlighted shifts in key glycolytic and amino acid pathways, indicating the cells' struggle to adapt to restricted glucose availability. Lipidomic profiling revealed alterations in lipid composition, implying disruptions in membrane integrity and signaling cascades., Conclusion: Our findings underscore the critical roles of glucose availability and SCD1 activity in sustaining cancer metabolic plasticity and growth. Simultaneously targeting these pathways emerges as a promising strategy to impede cancer progression. The comprehensive metabolomic and lipidomic analysis provides a detailed roadmap of molecular alterations induced by this combination treatment, that may help identify potential therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolic diseases, featured with dysregulated energy homeostasis, have become major global health challenges. Patients with metabolic diseases have high probability to manifest multiple complications in lipid metabolism, e.g. obesity, insulin resistance and fatty liver. Therefore, targeting the hub genes in lipid metabolism may systemically ameliorate the metabolic diseases, along with the complications. Stearoyl-CoA desaturase 1(SCD1) is a key enzyme that desaturates the saturated fatty acids (SFAs) derived from de novo lipogenesis or diet to generate monounsaturated fatty acids (MUFAs). SCD1 maintains the metabolic and tissue homeostasis by responding to, and integrating the multiple layers of endogenous stimuli, which is mediated by the synthesized MUFAs. It critically regulates a myriad of physiological processes, including energy homeostasis, development, autophagy, tumorigenesis and inflammation. Aberrant transcriptional and epigenetic activation of SCD1 regulates AMPK/ACC, SIRT1/PGC1α, NcDase/Wnt, etc, and causes aberrant lipid accumulation, thereby promoting the progression of obesity, non-alcoholic fatty liver, diabetes and cancer. This review critically assesses the integrative mechanisms of the (patho)physiological functions of SCD1 in metabolic homeostasis, inflammation and autophagy. For translational perspective, potent SCD1 inhibitors have been developed to treat various types of cancer. We thus discuss the multidisciplinary advances that greatly accelerate the development of SCD1 new inhibitors. In conclusion, besides cancer treatment, SCD1 may serve as the promising target to combat multiple metabolic complications simultaneously., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Previous studies reported that pirfenidone (PFD) is associated with liver disease. However, the effects of pirfenidone on energy metabolism and hepatic lipid accumulation are still poorly understood., Methods: In this study, C57BL/6J mice were randomly divided into two groups, and fed a normal chow diet (NCD) or a high-fat diet (HFD) for 16 weeks. At the end of the eighth week, half of the mice fed on both diets were treated with PFD. Biochemical and lipid metabolism-related indices were analyzed. Furthermore, Hepa 1-6 cells and mouse primary hepatocytes (MPHs) were incubated with PFD with or without free fatty acid (FFA) treatment. Then, stattic (a p-STAT3 inhibitor) or Ad-shSTAT3 was used to further elucidate the effects of Signal Transducer and Activator of Transcription 3 (STAT3) signaling on PFD regulation of hepatic steatosis., Results: PFD ameliorated obesity and hepatic lipid deposition in HFD mice by decreasing stearoyl-CoA desaturase 1 (SCD1) expression and upregulating p-STAT3 in the liver. In Hepa 1-6 cells and MPHs, PFD also down-regulated the expression of SCD1. STAT3 inhibition treatment eliminated the benefits of PFD on both SCD1 and hepatic steatosis., Conclusion: In summary, our data reveal that PFD may play an important role in mitigating hepatic steatosis in a STAT3-SCD1-dependent manner., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In this study, we aimed to explore the molecular role of Deltex E3 ubiquitin ligase 4 (DTX4) in thyroid cancer (TC) both in vitro and in vivo. The expression level of DTX4 in TC tissues was compared using The Cancer Genome Atlas (TCGA) database. We subsequently evaluated cell proliferation and migration in DTX4 knock down or DTX4 overexpression TC cell lines (TPC-1 and K1) by CCK-8, cell colony formation, and transwell assays. RNA sequencing and KEGG analysis were employed to identify potential genes that interact with DTX4. Our results showed that DTX4 was expressed at higher levels in both TC tissues and cells compared to normal controls. Knock down of DTX4 expression significantly inhibited TC cell progression in vitro. Furthermore, knockdown of endogenous DTX4 by shDTX4 markedly abrogated tumor growth, with significantly smaller tumor size and lower tumor weight in the shDTX4 group compared to the shCtrl group. Conversely, overexpression of DTX4 enhanced TC cell proliferation and migration. Through RNA sequencing, we identified 590 Differentially Expressed Genes (DEGs), with stearoyl-CoA desaturase 1 (SCD) ranking as the top gene. A positive correlation between DTX4 and SCD was observed in TC samples. Additionally, treatment with an SCD inhibitor, A939572, significantly rescued the enhanced growth effect induced by DTX4 overexpression. In conclusion, this study demonstrated that DTX4 promotes TC progression through SCD, indicating that the DTX4/SCD axis could be a promising target for TC therapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Niche for stem cells profoundly influences their maintenance and fate during tissue homeostasis and pathological disorders; however, the underlying mechanisms and tissue-specific features remain poorly understood. Here, it is reported that fatty acid desaturation catabolized by stearoyl-coenzyme A desaturase 1 (SCD1) regulates hair follicle stem cells (HFSCs) and hair growth by maintaining the bulge, niche for HFSCs. Scd1 deletion in mice results in abnormal hair growth, an effect exerted directly on keratin K14 + keratinocytes rather than on HFSCs. Mechanistically, Scd1 deficiency impairs the level of integrin α6β4 complex and thus the assembly of hemidesmosomes (HDs). The disruption of HDs allows the aberrant activation of focal adhesion kinase and PI3K in K14 + keratinocytes and subsequently their differentiation and proliferation. The overgrowth of basal keratinocytes results in downward extension of the outer root sheath and interruption of bulge formation. Then, inhibition of PI3K signaling in Scd1 -/- mice normalizes the bulge, HFSCs, and hair growth. Additionally, supplementation of oleic acid to Scd1 -/- mice reestablishes HDs and the homeostasis of bulge niche, and restores hair growth. Thus, SCD1 is critical in regulating hair growth through stabilizing HDs in basal keratinocytes and thus sustaining bulge for HFSC residence and periodic activity., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The gut bacterial strains and their metabolites have been shown to play a significant role in obesity, but the molecular mechanisms underlying this association are largely unresolved. Obesity is a multifactorial problem and is controlled by various mechanisms and pathways to produce and store fat cells. Bacteriocins are secondary metabolites produced by gut bacteria to defend themselves against their competitors. Recently, they have gained great attention due to their role in metabolic disorders, including obesity. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme involved in the differentiation of adipocytes. The aim of this study is to show the regulation of SCD1 by bacteriocins and thus their importance in obesity control. We screened the human gut bacteriome for the presence of bacteriocins, predicted their structures, and showed their inhibitory role by molecular docking with SCD1. Further, to confirm the docking results, MDS of six top scoring SCD1-bacteriocin complexes were carried out for 100 ns. These six bacteriocins namely, Plantaricin S-beta, Carnolysin, Lactococcin B, Bacteriocin Iic, Plantaricin N, and Thermophilin A, with strong binding affinities, are primarily produced by bacterial strains from the Lactobacillaeacea family. These findings can be the basis of further experiments for enhanced understanding of the underlying mechanisms for obesity control, specifically bacteriocins driven regulation of the SCD1 enzyme. In addition, a consortium of bacterial strains producing these bacteriocins can be developed and used as probiotics for the amelioration of obesity and other metabolic complications.Communicated by Ramaswamy H. Sarma.

The objective of the study was to elucidate the stearoyl-coenzyme A desaturase (SCD1)-dependent gene network of c9, t11-CLA biosynthesis in MAC-T cells from an energy metabolism perspective. The cells were divided into the CAY group (firstly incubated with CAY10566, a chemical inhibitor of SCD1, then incubated with trans-11-octadecenoic acid, (TVA)), the TVA group (only TVA), and the control group (without CAY, TVA). The c9, t11-CLA, and TVA contents were determined by gas chromatography. The mRNA levels of SCD1 and candidate genes were analyzed via real-time PCR. Tandem mass tag (TMT)-based quantitative proteomics, bioinformatic analysis, parallel reaction monitoring (PRM), and small RNA interference were used to explore genes involved in the SCD1-dependent c9, t11-CLA biosynthesis. The results showed that the SCD1 deficiency led by CAY10566 blocked the biosynthesis of c9, t11-CLA. In total, 60 SCD1-related proteins mainly involved in energy metabolism pathways were primarily screened by TMT-based quantitative proteomics analysis. Moreover, 17 proteins were validated using PRM analysis. Then, 11 genes were verified to have negative relationships with SCD1 after the small RNA interference analysis. Based on the above results, we concluded that genes involved in energy metabolism pathways have an impact on the SCD1-dependent molecular mechanism of c9, t11-CLA biosynthesis.

Purpose: This study aimed to disclose the antidiabetic mechanisms of Rehmanniae Radix (RR). Methods: The antidiabetic effect of RR was studied in Streptozocin (STZ)-induced diabetes mellitus (DM) rats and HepG2 cells with insulin resistance (IR). Antidiabetic targets and signaling pathways of RR were confirmed by the network pharmacology and transcriptome analysis as well as HK2 cells induced by high glucose (HG). Results: After the DM rats were administrated RR extract (RRE) for 4 weeks, their body weight was 10.70 ± 2.00% higher than those in the model group, and the fasting blood glucose (FBG), AUC of the oral glucose tolerance test, and insulin sensitivity test values were 73.23 ± 3.33%, 12.31 ± 2.29%, and 13.61 ± 5.60% lower in the RRE group, respectively. When compared with the model group, an increase of 45.76 ± 3.03% in the glucose uptake of HepG2 cells with IR was seen in the RRE group. The drug (RR)-components-disease (DM)-targets network with 18 components and 58 targets was established. 331 differentially expressed genes (DEGs) were identified. TRPV1 and SCD1 were important DEGs by the intersectional analysis of network pharmacology and renal transcriptome. The TRPV1 overexpression significantly inhibited apoptosis and oxidative stress of the HK2 cells induced by HG, while SCD1 overexpression induced apoptosis and oxidative stress of the HK2 cells induced by low and high glucose. When compared to the HG group, the mRNA and protein expressions of TRPV1 in the presence of RRE (100 μg/ml) increased by 3.94 ± 0.08 and 2.83 ± 0.40 folds, respectively. Conclusion: In summary, RR displayed an inspiring antidiabetic effect by reducing FBG and IR, upregulating the mRNA and protein expressions of TRPV1, and downregulating mRNA expression of SCD1. Induction of TRPV1 and inhibition of SCD1 by RR was possibly one of its antidiabetic mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Zhu, Liu, Wang, Yang, Cao, Yang, Du, Yang, Liang, Hu and Ma.)

The primary regulatory gene for fatty acid synthesis, stearoyl-CoA desaturase 1 (SCD1), has been linked to the progression of several malignancies. Its role in cervical cancer remains unclear till now. This paper aimed to explore the role and mechanism of SCD1 in cervical cancer. The GEPIA database was used to perform a bioinformatics analysis of the role of SCD1 in cervical cancer staging and prognosis. The influences of SCD1 knockdown on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) progress were then investigated. Following transcription factor Kruppel like factor 9 (KLF9) was discovered to be negatively correlated with SCD1, the regulatory role of KLF9 in the effects of SCD1 on cervical cancer cells and the signaling pathway was evaluated. According to the GEPIA database, SCD1 level was associated with the cervical cancer stage, the overall survival level, and the disease-free survival level. Cell proliferation, migration, invasion, and EMT progress were all hindered when its expression was knocked down. Novelty, KLF9 reversed the effects of SCD1 on cells, as well as the Akt/glycogen synthase kinase 3β (GSK3β) signaling pathway. Together, SCD1 was negatively regulated by KLF9 and it activated the Akt/GSK3β signaling pathway to promote the malignant progression of cervical cancer cells. Developing SCD1 inhibitors offers novel ideas for the biological treatment of cervical cancer.

Goat milk contains a rich source of nutrients, especially unsaturated fatty acids. However, the regulatory mechanism of milk fat and fatty acid synthesis remains unclear. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme catalyzing monounsaturated fatty acid synthesis and is essential for milk lipid metabolism. To explore milk lipid synthesis mechanism in vivo , SCD1 -knockout goats were generated through CRISPR/Cas9 technology for the first time. SCD1 deficiency did not influence goat growth or serum biochemistry. Plasma phosphatidylcholines increased by lipidomics after SCD1 knockout in goats. Whole-blood RNA-seq indicated alterations in biosynthesis of unsaturated fatty acid synthesis, cAMP, ATPase activity, and Wnt signaling pathways. In SCD1- knockout goats, milk fat percentage and unsaturated fatty acid levels were reduced but other milk components were unchanged. Milk lipidomics revealed decreased triacylglycerols and diacylglycerols levels, and the differential abundance of lipids were enriched in glycerolipid, glycerophospholipids, and thermogenesis metabolism pathways. In milk fat globules, the expression levels of genes related to fatty acid and TAG synthesis including SREBP1 were reduced. ATP content and AMPK activity were promoted, and p-p70S6K protein level was suppressed in SCD1- knockout goat mammary epithelial cells, suggesting that SCD1 affected milk lipid metabolism by influencing AMPK-mTORC1/p70S6K-SREBP1 pathway. The integrative analysis of gene expression levels and lipidomics of milk revealed a crucial role of SCD1 in glycerolipids and glycerophospholipids metabolism pathways. Our observations indicated that SCD1 regulated the synthesis of milk fat and unsaturated fatty acid in goat by affecting lipid metabolism gene expression and lipid metabolic pathways. These findings would be essential for improving goat milk nutritional value which is beneficial to human health.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death with few therapeutic treatment options. Under adverse tumor microenvironment, autophagy is an important mechanism of metabolic adaptations to sustain the survival and proliferation of tumor cells. Therefore, targeting autophagic activity represents a promising opportunity for NSCLC treatment. Here, we found that amodiaquine (AQ) increased autophagosome numbers and LC3BII and p62 at protein levels in A549 lung cancer cells suggesting the blockade of autophagic flux by AQ. To identify the key metabolic vulnerability associated with autophagy inhibition by AQ treatment, we then performed transcriptomics analysis in the presence or absence of AQ in A549 lung cancer cells and found stearoyl-CoA desaturase 1 (SCD1) was one of the most highly upregulated with AQ exposure. The induction of SCD1 by AQ exposure at both protein and mRNA level suggests that SCD1 could represent a potential therapeutic target of AQ treatment. Treatment of AQ in combination with SCD1 inhibition by A939572 demonstrated robust synergistic anti-cancer efficacy in cell proliferation assay and a lung cancer mouse xenograft model. Taken together, our study identified SCD1 could be a new therapeutic target upon autophagy inhibition by AQ exposure. Combinational treatment of autophagy inhibition and SCD1 inhibition achieves synergistic anti-tumor effect both in vitro and in vivo. This combinational approach could be a promising strategy for NSCLC treatment.

Apart from the known associations between arachidonic acid (AA), weight gain, and neurological and immune function, AA exposure leads to alterations in global and gene-specific DNA methylation (DNAm) and fatty acid (FA) content in human cultured cells. However, it is unknown as to whether the latter effects occur in vivo and are maintained over extended periods of time and across generations. To address this issue, we asked whether AA supplementation for three consecutive generations (prior to coitus in sires or in utero in dams) affected offspring growth phenotypes, in addition to liver DNAm and FA profiles in mice. Twelve-week-old BALB/c mice were exposed daily to AA dissolved in soybean oil (vehicle, VH), or VH only, for 10 days prior to mating or during the entire pregnancy (20 days). On average, 15 mice were supplemented per generation, followed by analysis of offspring body weight and liver traits (x average = 36 and 10 per generation, respectively). Body weight cumulatively increased in F2 and F3 offspring generations and positively correlated with milligrams of paternal or maternal offspring AA exposure. A concomitant increase in liver weight was observed. Notably, akin to AA-challenged cultured cells, global DNAm and cis-7-hexadecenoic acid (16:1n-9), an anti-inflammatory FA that is dependent on stearoyl-CoA desaturase 1 (SCD1) activity, increased with milligrams of AA exposure. In accordance, liver Scd1 promoter methylation decreased with milligrams of germline AA exposure and was negatively correlated with liver weight. Our results show that mice retain cellular memories of AA exposure across generations that could potentially be beneficial to the innate immune system.

Purpose: Deleted in breast cancer 1 (DBC1) ablation causes obesity, and stearoyl-CoA desaturase 1 (SCD1) induces the biosynthesis of monounsaturated fatty acids. This study examined whether voluntary wheel running (VWR) alters SCD-1 and DBC1 protein levels in the liver of leptin-deficient ob/ob mice., Methods: Twenty-five Ob/Ob mice were divided into two groups (ob/ob-Sed and ob/ob-Ex). The expression of DBC1 and SCD1 in the mouse liver was determined using western blotting., Results: After 10 weeks, VWR significantly reduced body weight without affecting the fatty acid synthase and CD36 protein levels. The average daily running distance was 4.0±1.0 km/day. This improvement was associated with changes in the hepatic SCD1 and DBC1 levels. Hepatic SCD-1 protein levels increased significantly, and DBC1 protein levels decreased in ob/ob-Sed animals. On the other hand, VWR inhibited the obesity-induced increase in SCD1 expression and impaired the obesity-induced decrease in DBC1 expression in the liver of leptin-deficient ob/ob mice., Conclusion: This is the first study showing that VWR has strong effects on hepatic SCD1 and DBC1 in ob/ob mice, and provides key insights into the effects of exercise on obesity.

Background: Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control., Aim: To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet (0.1MCD)] after treatment with Aramchol., Methods: Isolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with 13 C-uniformly labeled glucose. For the in vivo part of the study, male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites., Results: Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid (FA) synthesis and oxidation [P-ACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation (NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid (TCA) cycle (MDH2, SUCLA2, and SUCLG2), and ribosome (P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with 13 C-uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5P/Xyl5P., Conclusion: Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation., Competing Interests: Conflict-of-interest statement: Dr. Mato is a Galmed Pharmaceuticals and OWL Metabolomics consultant and/or speaker. Dr. Hayardeny and Dr. Tzivirkun are Galmed Pharmaceuticals employees. Dr. Iruarrizaga-Lejarreta and Dr. Alonso are OWL Metabolomics employees. All other authors have nothing to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Stearoyl-CoA desaturases (SCD) are endoplasmic reticulum (ER)-associated enzymes that catalyze the synthesis of the monounsaturated fatty acids (MUFAs). As such, SCD play important roles in maintaining the intracellular balance between saturated fatty acid (SFAs) and MUFAs. The roles of SCD in CD4 + T-helper cell responses are currently unexplored. Here, we have found that murine and human follicular helper T (T FH ) cells express higher levels of SCD compared to non-T FH cells. Further, the expression of SCD in T FH cells is dependent on the T FH lineage-specification transcription factor BCL6. We found that the inhibition of SCD impaired T FH cell maintenance and shifted the balance between T FH and follicular regulatory T (T FR ) cells in the spleen. Consequently, SCD inhibition dampened germinal center B-cell responses following influenza immunization. Mechanistically, we found that SCD inhibition led to increased ER stress and enhanced T FH cell apoptosis in vitro and in vivo. These results reveal a possible link between fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, autoimmunity., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: Metabolic syndrome (MetS) diagnosed in the dialysis patients is increasingly reported which worsens the prognosis of the renal diseases. The relationship of SCD1 with MetS is largely unknown. The purpose of this study was to investigate the relationship between SCD1 polymorphism and MetS in dialysis patients. Methods: A cross-sectional study was conducted on 323 Chinese dialysis patients, and the correlation between the seven SNPs of SCD1 gene (rs10883465, rs2060792, rs1502593, rs522951, rs3071, rs3978768 and rs1393492) and MetS was analyzed. Results: One tag-SNP (rs1393492) has significantly associated with the prevalence of MetS. Dialysis patients with rs1393492 AA genotype of SCD1 are more prone to MetS (p = 0.021). Conclusion: This study shows that the rs1393492 variations of SCD1 gene are related with the development of MetS in Chinese dialysis patients.

Bisphenol A (BPA), a major plasticizers that are commonly used for lining of beverage or food-storage containers, has been shown to increase cholesterol levels with molecular mechanism not clear. The present study was aimed to investigate the effects of BPA exposure on liver cholesterol synthesis and hepatic steatosis in male C57BL/6 mice and its underlying mechanisms. Male C57BL/6 mice were exposed to different doses (50, 500 and 5000 μg/kg/day) of BPA through diet for 16 weeks. Exposure to low doses (50 and 500 μg/kg/day) of BPA increased hepatic cholesterol content and the expression levels of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and sterol regulatory element binding proteins-2 (SREBP-2). DNA methylation analysis further showed that mice exposed to low-dose BPA decreased the DNA methylation levels of SREBP-2. Moreover, low doses of BPA exposure increased the expression levels of SREBP-1c and stearoyl-CoA desaturase 1 in the liver, and induced hepatic lipid synthesis and fat accumulation. Our results suggest that low-dose BPA exposure could induce hepatic cholesterol synthesis through decreasing the DNA methylation levels of SREBP-2 and subsequently up-regulating the expression of genes related to cholesterol synthesis in the liver, which causes cholesterol accumulation and further induces liver lipid synthesis and hepatic steatosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lipid metabolism is associated with colon cancer prognosis and incidence. Stearoyl-CoA desaturase 1 (SCD1), which converts fully saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), has been suggested as a vulnerable target for selective elimination of cancer stem cells (CSCs). However, the clinical significance and physiological role of SCD1 in CSCs has not been well demonstrated. Here, we showed the clinical and biochemical relevance of blocking SCD1 to target CSCs by analyzing human colon cancer data from TCGA and through lipidomic profiling of CSCs with or without SCD1 inhibition using mass spectrometry. Positive associations between SCD1 expression and colorectal cancer patient clinical status and the expression of CSC-related genes (WNT and NOTCH signaling) were found based on TCGA data analysis. Lipidomic profiling of CSCs and bulk cancer cells (BCCs) using mass spectrometry revealed that colon CSCs contained a distinctive lipid profile, with higher free MUFA and lower free SFA levels than in BCCs, suggesting that enhanced SCD1 activity generates MUFAs that may support WNT signaling in CSCs. In addition, all identified phosphatidyl-ethanolamine-containing MUFAs were found at higher levels in CSCs. Interestingly, we observed lower phosphatidyl-serine (18:1/18:0), phosphatidyl-choline (PC; p-18:0/18:1)), and sphingomyelin (SM; d18:1/20:0 or d16:1/22:0) levels in CSCs than in BCCs. Of those, SCD1 inhibition, which efficiently diminished free MUFA levels, increased those specific PC and SM and MUFAs in CSCs promptly. These results suggest that these specific lipid composition is critical for CSC stem cell maintenance. In addition, not only free MUFAs, which are known to be required for WNT signaling, but also other phospholipids, such as SM, which are important for lipid raft formation, may mediate other cell signaling pathways that support CSC maintenance. Comparison of the lipidomic profiles of colon cancer cells with those of previously reported for glioma cells further demonstrated the tissue specific characteristics of lipid metabolism in CSCs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Backgrounds: The role of sphere-forming culture in enriching subpopulations with stem-cell properties in hepatocellular carcinoma (HCC) is unclear. The present study investigates its value in enriching cancer stem cells (CSCs) subpopulations and the mechanism by which HCC CSCs are maintained., Methods: HCC cell lines and fresh primary tumor cells were cultured in serum-free and ultra-low attachment conditions to allow formation of HCC spheres. In vitro and in vivo experiments were performed to evaluate CSC characteristics. Expression levels of CSC-related genes were assessed by qRT-PCR and the correlation between sphere formation and clinical characteristics was investigated. Finally, gene expression profiling was performed to explore the molecular mechanism underlying HCC CSC maintenance., Results: We found that both cell lines and primary tumor cells formed spheres. HCC spheres possessed the capacity for self-renewal, proliferation, drug resistance, and contained different subpopulations of CSCs. Of interest, 500 sphere-forming Huh7 cells or 200 primary tumor cells could generate tumors in immunodeficient animals. Sphere formation correlated with size, multiple tumors, satellite lesions, and advanced stage. Further investigation identified that the PPARα-SCD1 axis plays an important role in maintenance of the CSC properties of HCC sphere cells by promoting nuclear accumulation of β-Catenin. Inhibition of SCD1 interfered with sphere formation, down-regulated expression of CSC-related markers, and reduced β-Catenin nuclear accumulation., Conclusions: Sphere-forming culture can effectively enrich subpopulations with stem-cell properties, which are maintained through activation of the PPARα-SCD1 axis. Therefore, we suggest that targeting the SCD1-related CSC machinery might provide a novel insight into HCC treatment.

In mammalian species, the Fatty Acid Desaturase (FADS) gene cluster includes FADS1 (∆5-desaturase), FADS2 (∆6-desaturase), and a third gene member, named FADS3. According to its high degree of nucleotide sequence homology with both FADS1and FADS2, FADS3 was promptly suspected by researchers in the field to code for a new mammalian membrane-bound fatty acid desaturase. However, no catalytic activity was attributed to the FADS3 protein for a decade, until the rat FADS3 protein was shown in vitro to be able to catalyze the unexpected ∆13-desaturation of trans-vaccenic acid, producing the trans11,cis13-conjugated linoleic acid isomer. This review summarizes the recent investigations establishing the FADS3 enzyme as a reliable mammalian trans-vaccenate ∆13-desaturase in vivo and tries to identify further unresolved issues that need to be addressed., (© 2019 S. Karger AG, Basel.)

SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Cis-9-conjugated, trans-11-conjugated linoleic acid (CLA) is known for its positive activities on human health. The synthesis of cis-9, trans-11 CLA in mammary glands is generally thought to be catalyzed by stearoyl-CoA desaturase 1 (SCD1), but this has not been rigorously established. In this study, we hypothesized that the inhibition of SCD1 (by CAY10566) would block the synthesis of cis-9, trans-11 CLA in bovine mammary alveolar cells (MAC-T) cells. Results showed that MAC-T cells incubated with 10 nM CAY10566 for 12 h (CAY) produced less cis-9, trans-11 CLA (p < 0.01), lower 14:1/(14:1 + 14:0)% (p < 0.01), more trans-11 18:1 (TVA) accumulation (p < 0.01), and reduced SCD1 mRNA levels (p < 0.01) compared with the control group (CON). Moreover, the mRNA abundances of sterol regulatory element-binding protein 1 [SREBPF1], acyl-CoA synthetase short-chain family member 2 [ACSS2], and lipin 1 [LPIN1] were significantly elevated when SCD1 was inhibited in the CAY group (p < 0.05). Taken together, CAY10566 inhibition of SCD1 resulted in lower cis-9, trans-11 CLA synthesis ability, and SREBF1, ACSSS2, and LPIN1 were negatively associated with SCD1. These findings not only provide the direct evidence that cis-9, trans-11 CLA synthesis is catalyzed by SCD1, but also help us understand the responses of MAC-T cells to SCD1 inhibition., (© 2018 AOCS.)

Scope: Sciadonic acid (Scia; 20:3Δ5,11,14) is a distinctive fatty acid (FA) with a polymethylene-interrupted double bond at C5. It is specifically found in seeds from gymnosperms such as pine nuts. Published papers describe a decrease in liver and plasma triacylglycerols in rats fed with this nutriment. The present study seeks to identify the action mechanism of Scia on triacylglycerol synthesis. In this way, its nutritional effect on FA metabolism involving the Stearoyl-CoA Desaturase 1 (SCD1) is investigated., Methods and Results: Scia is discerned in trace amount in various tissues of rats and in human serum. It is produced by Δ5-desaturation of 20:2n-6 in human transfected SH-SY5Y cell lines and also in rat hepatocytes. When Scia is incubated with cultured hepatocytes as a nutrient, the cellular FA profile is modified. In particular, the proportion of the monoenes (18:1n-9, 18:1n-7, 16:1n-7) are all decreased, correlating to the reduction of triacylglycerol amounts. This effect is mediated by the inhibition of SCD1 expression. Furthermore, Scia, as well as 20:3n-6 and 20:3n-9 but not 20:3n-3, strongly inhibit the SCD1 activity measured on liver microsomes., Conclusion: Overall, this study shows that Scia, despite its unusual structure, contributes to the FA metabolism and reduced triacylglycerol release by inhibiting SCD1 activity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: To evaluate the levels of miR-192-5p in non-alcoholic fatty liver disease (NAFLD) models and demonstrate the role of miR-192-5p in lipid accumulation., Methods: Thirty Sprague Dawley rats were randomly divided into three groups, which were given a standard diet, a high-fat diet (HFD), and an HFD with injection of liraglutide. At the end of 16 weeks, hepatic miR-192-5p and stearoyl-CoA desaturase 1 (SCD-1) levels were measured. MiR-192-5p mimic and inhibitor and SCD-1 siRNA were transfected into Huh7 cells exposed to palmitic acid (PA). Lipid accumulation was evaluated by oil red O staining and triglyceride assays. Direct interaction was validated by dual-luciferase reporter gene assays., Results: The HFD rats showed a 0.46-fold decrease and a 3.5-fold increase in hepatic miR-192-5p and SCD-1 protein levels compared with controls, respectively, which could be reversed after disease remission by liraglutide injection ( P < 0.01). The Huh7 cells exposed to PA also showed down-regulation and up-regulation of miR-192-5p and SCD-1 protein levels, respectively ( P < 0.01). Transfection with miR-192-5p mimic and inhibitor in Huh7 cells induced dramatic repression and promotion of SCD-1 protein levels, respectively ( P < 0.01). Luciferase activity was suppressed and enhanced by miR-192-5p mimic and inhibitor, respectively, in wild-type SCD-1 ( P < 0.01) but not in mutant SCD-1. MiR-192-5p overexpression reduced lipid accumulation significantly in PA-treated Huh7 cells, and SCD-1 siRNA transfection abrogated the lipid deposition aggravated by miR-192-5p inhibitor ( P < 0.01)., Conclusion: This study demonstrates that miR-192-5p has a negative regulatory role in lipid synthesis, which is mediated through its direct regulation of SCD-1., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.

Most cancer cells are characterized by elevated lipid biosynthesis. The rapid proliferation of cancer cells requires de novo synthesis of fatty acids. Stearoyl-CoA desaturase-1 (SCD1), a key enzyme for lipogenesis, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. Therefore, it has been studied as a candidate target for cancer therapy. In this study, we demonstrate the pharmacological properties of T-3764518, a novel and orally available small molecule inhibitor of SCD1. T-3764518 inhibited stearoyl-CoA desaturase-catalyzed conversion of stearoyl-CoA to oleoyl-CoA in colorectal cancer HCT-116 cells and their growth. Further, it slowed tumor growth in an HCT-116 and a mesothelioma MSTO-211H mouse xenograft model. Comprehensive lipidomic analyses revealed that T-3764518 increases the membrane ratio of saturated: unsaturated fatty acids in various lipid species such as phosphatidylcholines and diacylglycerols in both cultured cells and HCT-116 xenografts. Treatment-associated lipidomic changes were followed by activated endoplasmic reticulum (ER) stress responses such as increased immunoglobulin heavy chain-binding protein expression in HCT-116 cells. These T-3764518-induced changes led to an increase in cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptosis. Additionally, bovine serum albumin conjugated with oleic acid, an SCD1 product, prevented cell growth inhibition and ER stress responses by T-3764518, indicating that these outcomes were not attributable to off-target effects. These results indicate that T-3764518 is a promising new anticancer drug candidate., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The octadecadienoic conjugated linoleic acid (CLA) isomer with trans-11 and cis-13 double bonds (trans-11,cis-13 CLA) has been described in ruminant milk. For now, this specific CLA is suspected to derive exclusively from ruminal biohydrogenation of dietary α-linolenic acid. However, in rodents, the fatty acid desaturase 3 (FADS3) gene was recently shown to code for an enzyme able to catalyze the unexpected Δ13-desaturation of vaccenic acid, producing a Δ11,13-CLA with all the structural characteristics of the trans-11,cis-13 isomer, although no commercial standard exists for complete conclusive identification. Because the FADS3 gene has already been reported in bovine animals, we hypothesized in the present study that an alternative direct FADS3-catalyzed Δ13-desaturation of vaccenic acid in mammary tissue may therefore co-exist with α-linolenic acid biohydrogenation to explain the final ruminant milk trans-11,cis-13 CLA presence. Here, we first confirm that the FADS3 gene is present in ruminant mammal genomic sequence databases. Second, we demonstrate that the Δ11,13-CLA found in milk fat and the highly probable trans-11,cis-13 CLA isomer produced by rodent FADS3 possess exactly the same structural characteristics. Then, we show that bovine mammary MAC-T and BME-UV epithelial cells express both FADS3 and stearoyl-CoA desaturase 1 (SCD1) mRNA and are able to synthesize both the suspected trans-11,cis-13 CLA and cis-9,trans-11CLA (rumenic acid) isomers when incubated with vaccenic acid. Finally, the concomitant presence of the suspected trans-11,cis-13 CLA isomer with FADS3 mRNA was shown in goat mammary tissue, whereas both were conversely very low or even absent in goat liver. Therefore, this study provides several lines of evidence that, by analogy with rumenic acid, trans-11,cis-13 CLA may originate both from ruminal biohydrogenation and from direct FADS3-catalyzed Δ13-desaturation of vaccenic acid in mammary tissue., (Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Stearoyl-coenzyme A desaturase 1 (SCD1) is a pivotal enzyme in the biosynthesis of monounsaturated fatty acids (MUFA). It is tightly regulated by transcription factors that control lipogenesis. In nonruminants, liver X receptor α (LXRα) is a nuclear receptor and transcription factor that acts as a key sensor of cholesterol and lipid homeostasis. However, the mechanism whereby LXRα regulates the expression and transcriptional activity of SCD1 in ruminant mammary cells remains unknown. In this study with goat mammary epithelial cells (GMEC), the LXRα agonist T 4506585 (T09) markedly enhanced the mRNA expression of SCD1 and sterol regulatory element binding factor 1 (SREBF1). The concentrations of C16:1 and C18:1 and their desaturation indices also were increased by LXRα activation. However, knockdown of LXRα did not alter the mRNA expression of SCD1. Although SCD1 was repressed by SREBF1 knockdown, T09 significantly increased SCD1 expression. Further analysis revealed that the SCD1 promoter activity was activated by LXRα overexpression. The goat SCD1 promoter contains 2 LXR response elements (LXRE), 1 sterol response element (SRE), and 1 nuclear factor Y (NF-Y) binding site. Site-directed mutagenesis of LXRE1, LXRE2, or SRE alone did not eliminate the upregulation of SCD1 when LXRα was overexpressed. In contrast, when NF-Y alone or in combination with SRE was mutated simultaneously, the basal transcriptional activity of the SCD1 promoter was markedly decreased and did not respond to LXRα overexpression. Furthermore, when SREBF1 was knocked down, overexpression of LXRα did not affect the promoter activity of SCD1. Together, these data suggest that LXRα regulates the expression of SCD1 through increasing SREBP-1 abundance to promote interaction with SRE and NF-Y binding sites. The present study provides evidence that LXRα is involved in the synthesis of MUFA in the goat mammary gland through an indirect mechanism., (Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Palmitate (PA), stearate (SA), palmitoleate (PMA) and oleate (OA) are among the most abundant fatty acids (FAs) in adipose tissue (AT). These FAs differentially regulate AT inflammation by altering adipocyte signalling pathways and the secretion of proinflammatory cytokines. Intracellular levels of these FAs are controlled, in part, by stearoyl-CoA desaturase 1 (SCD1). Therefore, SCD1 may have an important role mediating FA-regulation of adipocyte inflammation. Given this, we hypothesized that the influence of PA, SA, PMA and OA on inflammation and cellular stress, as well as FA metabolism, would be exacerbated with reduced SCD1 activity. Real-time RT-PCR, immunoassays, gas chromatography and western blotting were used to examine the expression and secretion of common inflammatory markers, as well as FA profiles and markers of cellular stress, in 3T3-L1 adipocytes. FA treatments differentially affected inflammatory markers and FA profiles in SCD1-inhibited adipocytes. Specifically, SA significantly increased the expression of Ccl5 (5.3-fold) and Mcp-1 (3.2-fold), and the secretion of IL-6 (17.8-fold) and MCP-1 (4.0-fold) in SCD1-inhibited adipocytes compared to controls. The proinflammatory effects observed with SA are particularly notable given that SCD1-inhibited adipocytes increased elongation of PA to SA, as determined using U-(13)C-PA. The effects of PA, PMA and OA were not as substantial as those of SA, although PA did significantly increase Ccl5 (2.7-fold) and Mcp-1 (1.2-fold) expression in SCD1-inhibited adipocytes. None of the FAs altered markers of cellular stress. Collectively, these results emphasize the differential effects of individual FAs and highlight how SCD1 influences their regulation of adipocyte inflammation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the effect of ω-3 fatty acids on nonalcoholic fatty liver disease concerning hepatocyte lipid accumulation as well as apoptosis induced by free fatty acids (FFAs) and to explore the underlying mechanism involving autophagy., Methods: Hepatocytes were incubated with a mixture of free fatty acids (FFAs) to mimic in vitro lipotoxicity in the pathogenesis of nonalcoholic fatty liver disease, presented by lipid accumulation and cellular apoptosis. Chemical inhibitor or inducer of autophagy and genetic deficit cells, as well as ω-3 fatty acids were used as intervention. The autophagic role of ω-3 fatty acids was investigated using Western blot and immunofluorescence. The underlying mechanism of ω-3 fatty acids involving autophagy was preliminarily explored by quantitative real-time polymerase chain reaction and Western blot., Results: FFAs induce lipid accumulation and apoptosis in hepatocytes. Inhibition or genetic defect of autophagy increases lipid accumulation induced by FFA, whereas induction acts inversely. ω-3 Fatty acids reduced lipid accumulation and inhibited apoptosis induced by FFA. ω-3 Fatty acids induced autophagy by downregulating stearoyl-CoA desaturase 1 expression in hepatocytes., Conclusion: ω-3 Fatty acids exert protective effects on hepatocytes against lipotoxicity through induction of autophagy, as demonstrated by inhibition of lipid accumulation and apoptosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hepatic steatosis is associated with insulin resistance and metabolic syndrome because of increased hepatic triglyceride content. We have reported previously that deficiency of response gene to complement 32 (RGC-32) prevents high-fat diet (HFD)-induced obesity and insulin resistance in mice. This study was conducted to determine the role of RGC-32 in the regulation of hepatic steatosis. We observed that hepatic RGC-32 was induced dramatically by both HFD challenge and ethanol administration. RGC-32 knockout (RGC32(-/-)) mice were resistant to HFD- and ethanol-induced hepatic steatosis. The hepatic triglyceride content of RGC32(-/-) mice was decreased significantly compared with WT controls even under normal chow conditions. Moreover, RGC-32 deficiency decreased the expression of lipogenesis-related genes, sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase, and stearoyl-CoA desaturase 1 (SCD1). RGC-32 deficiency also decreased SCD1 activity, as indicated by decreased desaturase indices of the liver and serum. Mechanistically, insulin and ethanol induced RGC-32 expression through the NF-κB signaling pathway, which, in turn, increased SCD1 expression in a SREBP-1c-dependent manner. RGC-32 also promoted SREBP-1c expression through activating liver X receptor. These results demonstrate that RGC-32 contributes to the development of hepatic steatosis by facilitating de novo lipogenesis through activating liver X receptor, leading to the induction of SREBP-1c and its target genes. Therefore, RGC-32 may be a potential novel drug target for the treatment of hepatic steatosis and its related diseases., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

The conversion of saturated fatty acids (FAs) palmitate (16:0) and stearate (18:0) into monounsaturated FAs palmitoleate (16:1n-7) and oleate (18:1n-9) is catalyzed by stearoyl-CoA desaturase 1 (SCD1). These FAs represent the dominant constituents of adipocyte triacylglycerols (TAGs) and phospholipids (PLs). Given the critical role of SCD1 in lipid metabolism and the notable increase in its expression during adipogenesis, reductions in SCD1 activity have the potential to compromise the adipocyte's ability to accumulate lipid. The current study used thin-layer and gas chromatography to examine the content and FA composition of TAGs, PLs, cholesteryl esters, diacylglycerols and free fatty acids in SCD1-inhibited differentiating 3T3-L1 adipocyte cells. SCD1 inhibition reduced total cellular PL and TAG content concurrent with the down-regulation of genes involved in TAG and PL biosynthesis; however, the relative amount of PL was unaltered. While total DAG levels were increased ~2.7-fold in SCD1-inhibited adipocytes, this did not induce JNK activation; however, phosphorylated (Ser473) AKT was significantly reduced. As expected, total SFA and MUFA content were increased (~1.3-fold) and decreased (~4.0-fold). Further, SCD1 inhibition caused a ~2.2-fold increase and a ~8.3-fold decrease in total cellular 18:0 and 16:1n-7 levels, respectively. Similar changes were also seen in other lipid fractions. The levels of other FAs, including polyunsaturated FAs, were also changed in SCD1-inhibited adipocytes. Together, these results add to the existing body of knowledge regarding SCD1 function in adipocytes and highlight its important role in regulating global adipocyte lipid composition., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Three key genes, stearoyl-CoA desaturase-1 (SCD1), Δ6 fatty acyl desaturases (Fads2 (Δ6)) and elongase of very long-chain fatty acid 5 (ELOVL5) were firstly isolated and characterized from yellow catfish, Pelteobagrus fulvidraco. The protein sequence of yellow catfish SCD1 and Fads2 (Δ6) possessed all the characteristics of microsomal fatty acid Fads2 (Δ6), including three histidine boxes, two transmembrane regions and one N-terminal cytochrome b5 domain containing heme-binding motif. The protein sequence of yellow catfish ELOVL5 possessed characteristic features of ELOVL5, including multiple transmembrane regions, endoplasmic reticulum retention signal and a single histidine box. mRNAs of the three genes were expressed in various tissues, but their mRNA levels varied among tissues. Intraperitoneal injection of recombinant human leptin (rb-hLEP) inhibited mRNA expression of SCD1, but not Fads2 (Δ6) and ELOVL5. For the first time, our study cloned SCD1, Fads2 (Δ6) and ELOVL5 genes in Siluriformes and demonstrated their differential expression among tissues, and also differential regulation by leptin, which serves to increase our understanding on their physiological function in fish., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A method is described that allows noninvasive identification and quantitative assessment of lipid classes present in sebaceous excretions in rodents. The method relies on direct high-field proton NMR analysis of common group lipid protons in deuterated organic solvent extracts of fur. Extracts from as little as 15 mg of fur from rat, mouse, and hamster provided acceptable results on a 600 MHz NMR equipped with a cryogenically cooled proton-observe probe. In rats, sex- and age-related differences in lipid composition are larger than differences in fur collected from various body regions within an individual and much larger than interanimal differences in age- and sex-matched specimens. The utility of this method to noninvasively monitor drug-induced sebaceous gland atrophy in rodents is demonstrated in rats dosed with a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In this model, a 35% reduction in sebum lipids, extracted from fur, was observed. Finally, structural elucidation of cholesta-7,24-dien-3β-ol ester as the most prominent, previously unidentified sebum sterol ester in male Syrian hamsters is described. The utility of this method for drug and cosmetic safety and efficacy assessment is discussed., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Our recent genome-wide association study (GWAS) has identified 105 genome-wide significant SNPs for milk production traits. Of these, one SNP (rs109661298) for milk fat percentage is located within the first intron of the bovine EEF1D gene on BTA14, thus that the EEF1D gene was considered as a novel candidate in dairy cattle. Until now, however, its genomic organization remains undetermined yet and no studies of EEF1D in relation to milk production traits have been reported. To layout the groundwork for the validation of gene function in dairy cattle, we herein investigated its expression pattern in lactating dairy cows. With rapid amplification of 5' cDNA end (5' RACE), two novel alternatively spliced transcript variants of 1202bp and 2195bp were isolated in bovine mammary in lactation, named EEF1Da and EEF1Db (GenBank: KC190039 and KC190038KC190039KC190038). Such two variants contain the different first exon from each other (exon1a vs exon1b: 294bp vs 1287bp) with no overlap and the same remaining 7 exons. Coding sequence similarity between EEF1Da and EEF1Db and three of human EEF1D transcript variants were 85-88%. With semi-quantitative and quantitative real-time RT-PCR, we found that the mRNA level of EEF1Da was similar to the overall EEF1D mRNA and much higher than EEF1Db in the mammary of lactating cows, indicating EEF1Da functions as the dominant transcript variant to encode the EEF1D protein. Tissue expression pattern showed that the mRNA expression of EEF1D and EEF1Da in mammary gland was significantly higher compared with other 7 tissues (P<0.05, P<0.01) with the exception of EEF1D between mammary and lung. Together, our findings present the first report on the alternative splicing of the bovine EEF1D gene and provided basis for further investigation on function validation of EEF1D in dairy cattle., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In mammals, excess energy is stored primarily as triglycerides, which are mobilized when energy demands arise. This review mainly focuses on the role of long chain fatty acids (LCFAs) in regulating energy metabolism as ligands of peroxisome proliferator-activated receptors (PPARs). PPAR-alpha expressed primarily in liver is essential for metabolic adaptation to starvation by inducing genes for beta-oxidation and ketogenesis and by downregulating energy expenditure through fibroblast growth factor 21. PPAR-delta is highly expressed in skeletal muscle and induces genes for LCFA oxidation during fasting and endurance exercise. PPAR-delta also regulates glucose metabolism and mitochondrial biogenesis by inducing FOXO1 and PGC1-alpha. Genes targeted by PPAR-gamma in adipocytes suggest that PPAR-gamma senses incoming non-esterified LCFAs and induces the pathways to store LCFAs as triglycerides. Adiponectin, another important target of PPAR-gamma may act as a spacer between adipocytes to maintain their metabolic activity and insulin sensitivity. Another topic of this review is effects of skin LCFAs on energy metabolism. Specific LCFAs are required for the synthesis of skin lipids, which are essential for water barrier and thermal insulation functions of the skin. Disturbance of skin lipid metabolism often causes apparent resistance to developing obesity at the expense of normal skin function., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The severity of ethanol-induced liver injury is associated with oxidative stress and lipid accumulation in the liver. Core circadian clock is known to mediate antioxidative enzyme activity and lipid metabolism. However, the link between circadian clock and ethanol-induced hepatotoxicity remains unclear. Here we showed that extents of acute ethanol-induced liver injury and steatosis in mice exhibit circadian variations consistent with hepatic expression of Period (Per) genes. Mice lacking clock gene Per1 displayed less susceptible to ethanol-induced liver injury, as evidenced by lower serum transaminase activity and less severe histopathological changes. Ethanol-induced lipid peroxidation was alleviated in Per1-/- mice. However, Per1 deletion had no effect on antioxidants depletion caused by ethanol administration. Ethanol-induced triglycerides (TG) accumulation in the serum and liver was significantly decreased in Per1-/- mice compared with that in wild-type (WT) mice. Analysis of gene expression in the liver revealed peroxisome proliferators activated receptor-gamma (PPARγ) and its target genes related to TG synthesis are remarkably down-regulated in Per1-/- mice. HepG2 cells were treated with ethanol at 150 mM for 3 days. Per1 overexpression augmented lipid accumulation after treatment with ethanol in HepG2 cells, but had no effect on ethanol-induced oxidative stress. Expression of genes related to lipogenesis, including PPARγ and its target genes, was up-regulated in cells overexpressing Per1. In conclusion, these results indicated that circadian rhythms of ethanol-induced hepatotoxicity are controlled by clock gene Per1, and deletion of Per1 protected mice from ethanol-induced liver injury by decreasing hepatic lipid accumulation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Saturated free fatty acids (FFAs), such as palmitate, cause β-cell apoptosis whereas unsaturated FFAs, e.g. oleate, are not harmful. The toxicity of palmitate could be mediated through endoplasmic reticulum (ER) stress which triggers the activation of a signal responding cascade also called unfolded protein response (UPR). We investigated whether or not palmitate induced β-cell apoptosis through UPR activation and whether or not oleate as a monounsaturated fatty acid could counteract these effects., Methods: INS-1E β-cells were incubated with palmitate [0.5mM], oleate [1mM] or the combination [0.5/1mM] for 1, 6 and 24h. Viability and induction of apoptosis were measured by WST-1 assay and FITC-Annexin/PI-staining, respectively. Western blot analyses were performed for UPR specific proteins and mRNA expression of target molecules was determined by qPCR., Results: Palmitate significantly decreased viability (29±8.8%) of INS-1E β-cells compared to controls after 24h. Stimulation with oleate showed no effect on viability but the combination of oleate and palmitate improved viability compared to palmitate treated cells (55±9.3%) or controls (26±5.3%). The number of apoptotic cells was increased 2-fold after 24h incubation with palmitate compared to controls. Again, oleate showed no effect but in combination ameliorated the effect of palmitate to control level. Phosphorylation of eIF2α was increased after 6 and 24h incubation with palmitate. In contrast, oleate had no effect and in combination prevented phosphorylation of eIF2α. Increased Xbp1 splicing was visible already 6h after palmitate treatment and remained elevated at 24h. The combination with oleate abolished Xbp1 splicing. Interestingly, mRNA expression of the chaperones Bip, Pdi, Calnexin and Grp94 was not altered by FFA treatment. Only the proapoptotic transcription factor Chop was significantly enhanced by palmitate incubation. In accordance with sustained cell survival the combination as well as oleate alone, did not result in increased Chop levels compared to controls. In summary, we showed that oleate protects INS-1E β-cells from palmitate-induced apoptosis by the suppression of ER stress which was independent of chaperone activation., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Adiponectin (Ad) plays a crucial role in hepatic lipid metabolism. However, the regulating mechanism of hepatic lipid metabolism by Ad in dairy cows is unclear. Hepatocytes from a newborn female calf were cultured in vitro and treated with different concentrations of Ad and BML-275 (an AMPKα inhibitor). The results showed that Ad significantly increased the expression of two Ad receptors. Furthermore, the phosphorylation and activity of AMPKα, as well as the expression levels and transcriptional activity of peroxisome proliferator activated receptor-α (PPARα) and its target genes involved in lipid oxidation, showed a corresponding trend of upregulation. However, the expression levels and transcriptional activity of sterol regulatory element binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP) decreased in a similar manner. When BML-275 was added, the p-AMPKα level as well as the expression and activity of PPARα and its target genes were significantly decreased. However, the expression levels of SREBP-1c, ChREBP and their target genes showed a trend of upregulation. Furthermore, the triglyceride (TG) content was significantly decreased in the Ad-treated groups. These results indicate that Ad activates the AMPK signaling pathway and mediates lipid metabolism in bovine hepatocytes cultured in vitro by promoting lipid oxidation, suppressing lipid synthesis and reducing hepatic lipid accumulation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Changes in fatty acid (FA) and glycerophospholipid (GPL) metabolism associated with cell cycle entry are not fully understood. In this study FA-GPL remodeling was investigated in resting and proliferating primary human T cells. Significant changes were measured in the composition and distribution of FAs in GPLs following receptor activation of human T cells. The FA distribution of proliferating T cells was very similar to that of the human Jurkat T cell line and when the stimulus was removed from proliferating T cells, they stopped proliferating and the FA distribution largely reverted back to that of resting T cells. The cellular content of saturated and monounsaturated FAs was significantly increased in proliferating cells, which was associated with an induction of FA synthase and stearoyl-CoA desaturase-1 gene expression. Additionally, cellular arachidonate was redistributed in GPLs in a distinct pattern that was unlike any other FAs. This redistribution was associated with an induction of CoA-dependent and CoA-independent remodeling. Accordingly, significant changes in the expression of several acyl-CoA synthetases, lysophospholipid acyltransferases, and phospholipase A2 were measured. Overall, these results suggest that metabolic pathways are activated in proliferating T cells that may represent fundamental changes associated with human cell proliferation.

Black chokeberry (Aronia melanocarpa) is a rich source of polyphenols. The hypolipidemic effects of polyphenol-rich black chokeberry extract (CBE) have been reported, but underlying mechanisms have not been well characterized. We investigated the effect of CBE on the expression of genes involved in intestinal lipid metabolism. Caco-2 cells were incubated with 50 or 100 μg/ml of CBE for 24 h for quantitative realtime polymerase chain reaction analysis. Expression of genes for cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase and sterol regulatory element binding protein 2), apical cholesterol uptake (Niemann-Pick C1 Like 1 and scavenger receptor class B Type 1) and basolateral cholesterol efflux [ATP-binding cassette transporter A1 (ABCA1)] was significantly decreased by CBE compared with control. Western blot analysis confirmed that CBE inhibited expression of these proteins. In contrast, CBE markedly induced mRNA and/or protein levels of ABCG5 and ABCG8 that mediate apical cholesterol efflux to the intestinal lumen. Furthermore, CBE significantly increased mRNA and protein levels of low-density lipoprotein (LDL) receptor, and cellular LDL uptake. Expression of genes involved in lipid metabolism and lipoprotein assembly, including sterol regulatory element-binding protein 1c, fatty acid synthase and acyl-CoA oxidase 1, was significantly decreased by CBE in a dose-dependent manner. Concomitantly, CBE significantly increased sirtuin 1, 3 and 5 mRNA levels, while it decreased SIRT-2. Our data suggest that hypolipidemic effects of CBE may be attributed, at least in part, to increased apical efflux of LDL-derived cholesterol and to decreased chylomicron formation in the intestine; and specific isoforms of SIRT may play an important role in this process., (Copyright © 2013 Elsevier Inc. All rights reserved.)