stearoyl-CoA Desaturase Research Articles

α-Tocopherol-13'-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation.

α-Tocopherol-13'-carboxychromanol (α-T-13'-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G0/G1 cell cycle arrest and apoptosis in macrophages triggered by α-T-13'-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13'-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13'-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13'-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1).

ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance.

Stearoyl-CoA Desaturase 1 as a Therapeutic Biomarker: Focusing on Cancer Stem Cells.

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity.

Krüppel-like factor 4 (KLF4) facilitates lipid production in immortalized human sebocytes via regulating the expression of SREBP1

BackgroundAcne is associated with the excessive production of sebum, a complex mixture of lipids, in the sebaceous glands. The transcription factor Krüppel-like factor 4 (KLF4) plays an important role in skin morphogenesis, but its role in sebum production by sebocytes is not well known. PurposeIn this study, we investigated the possible action mechanism of KLF4 during calcium-induced lipogenesis in immortalized human sebocytes. MethodsSebocytes were treated with calcium, and lipid production was confirmed by thin-layer chromatography (TLC) and Oil Red O staining. To investigate the effect of KLF4, sebocytes were transduced with the KLF4-overexpressing adenovirus, and then lipid production was evaluated. ResultsCalcium treatment resulted in increased sebum production in terms of squalene synthesis in sebocytes. In addition, calcium increased the expression of lipogenic regulators such as sterol-regulatory element binding protein 1 (SREBP1), sterol-regulatory element binding protein 2 (SREBP2), and stearoyl-CoA desaturase (SCD). Similarly, the expression of KLF4 was increased by calcium in sebocytes. To investigate the effect of KLF4, we overexpressed KLF4 in sebocytes using recombinant adenovirus. As a result, KLF4 overexpression increased the expression of SREBP1, SREBP2, and SCD. Parallel to this result, lipid production was also increased by KLF4 overexpression. Chromatin immunoprecipitation revealed the binding of KLF4 to the SREBP1 promoter, indicating that KLF4 may directly regulate the expression of lipogenic regulators. ConclusionThese results suggest that KLF4 is a novel regulator of lipid production in sebocytes.

MTOR Plays a Conserved Role in Regulation of Nutritional Metabolism in Bivalve Sinonovacula constricta

The mammalian target of rapamycin (mTOR) has been shown to play a central role in regulating cell growth and metabolism. However, little is known about the function of mTOR in nutrient metabolism in bivalve mollusks. In this study, the role of mTOR in the regulation of nutrient metabolism was investigated in Sinonovacula constricta. First, the activation of mTOR was assayed after starvation and refeeding. Afterwards, the role of mTOR in the regulation of nutrient metabolism was investigated using an activator (MHY1485) or inhibitor (rapamycin) of mTOR. The open reading frame of the S. constricta mTOR is 7416 bp in length and encodes a polypeptide consisting of 2471 amino acids. The mTOR amino acid sequence of S. constricta was highly conserved when compared with other species and had a close evolutionary relationship with the TOR proteins of Crassostrea gigas and Lingula anatine. mTOR was expressed in the intestine, exhalent siphon, labial palppus, muscle, inhalent siphon, gill, mantle, digestive land, and gonad tissue of S. constricta, with the highest expression in muscle. During starvation, the level of phosphorylated mTOR protein was relatively low, and the ratio of LC3II/LC3I protein and the AMPKα mRNA level significantly increased with the increase in starvation time. After feeding, the level of phosphorylated mTOR protein increased from 0.13 to 0.56, and the ratio of LC3II/I protein and AMPKα mRNA level decreased from 1.17 to 0.38. MHY1485 significantly increased the level of phosphorylated 4E-BP1 and significantly decreased the ratio of LC3II/I proteins. Furthermore, MHY1485 significantly increased the mRNA level of the glucose metabolism-related gene glucokinase (GK), significantly decreased the mRNA expression of the G6P gene, and significantly increased the mRNA expression of the lipid synthesis-related genes sterol-regulatory element-binding protein (SREBP) and stearoyl-CoA desaturase (SCD). Rapamycin significantly reduced the level of phosphorylated 4E-BP1 and the mRNA expression of mTOR, and the expression level of phosphorylated 4EBP1 decreased from 0.97 to 0.28. Meanwhile, it also significantly reduced the mRNA expression of glucose metabolism-related genes GK, pyruvate kinase (PK), glucose transporter 1 (GLUT1), and G6P, as well as lipid synthesis-related genes SCD and acetyl-CoA carboxylase (ACC). These results indicate a conserved role of mTOR in regulating nutritional metabolism, including glucose metabolism, lipid synthesis, and autophagy in S. constricta.

Green Tea and Java Pepper Mixture Prevents Obesity by Increasing Energy Expenditure and Modulating Hepatic AMPK/MicroRNA-34a/370 Pathway in High-Fat Diet-Fed Rats.

This study was performed to evaluate the anti-obesity effects of green tea and java pepper mixture (GJ) on energy expenditure and understand the regulatory mechanisms of AMP-activated protein kinase (AMPK), microRNA (miR)-34a, and miR-370 pathways in the liver. Sprague-Dawley rats were divided into four groups depending on the following diets given for 14 weeks: normal chow diet (NR), 45% high-fat diet (HF), HF + 0.1% GJ (GJL), and HF + 0.2% GJ (GJH). The results revealed that GJ supplementation reduced body weight and hepatic fat accumulation, improved serum lipids, and increased energy expenditure. In the GJ-supplemented groups, the mRNA levels of genes related to fatty acid syntheses, such as a cluster of differentiation 36 (CD36), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) were downregulated, and mRNA levels of peroxisome proliferator-activated receptor alpha (PPARα), carnitine/palmitoyl-transferase 1 (CPT1), and uncoupling protein 2 (UCP2), which participate in fatty acid oxidation, were upregulated in the liver. GJ increased the AMPK activity and decreased the miR-34a and miR-370 expression. Therefore, GJ prevented obesity by increasing energy expenditure and regulating hepatic fatty acid synthesis and oxidation, suggesting that GJ is partially regulated through AMPK, miR-34a, and miR-370 pathways in the liver.

61 Altering Fatty Acid Ratios to Regulate Adipocyte HypertrophyIn Vitro

Abstract Adipose tissue deposition in cattle can prove advantageous and detrimental when grading carcasses. Intramuscular fat (IMF) deposition, or marbling, can enhance sensory qualities such as tenderness and flavor, whereas subcutaneous fat deposition reduces carcass red meat yield. Little is known about how different mixtures of fatty acids influence adipocyte hypertrophy in vitro. Primary preadipocytes were isolated from subcutaneous fat harvested from Angus-cross yearling steers. Preadipocytes were propagated and differentiated into adipocytes. Then eight different mixtures with pairs of different fatty acids (C16:0, C18:0, C18:1cis-9, and C18:2) at varying ratios were added to the cultures. Each individual mix was applied at the same total molar concentration. At the end of the 4-day treatment period, cells were harvested for future RNA extraction and fatty acid analysis. The expression of critical adipogenic and lipogenic genes was evaluated. Mixes exhibited differences in total fatty acid content (ug) which would not only confirm that the adipocytes are differentiated but also translates to potential differences in hypertrophic growth between mixes (P < 0.05). The control exhibited significantly different fatty acid binding protein-4 (FABP4) and stearoyl co-A desaturase-1 (SCD-1) expressions in comparison with all other mixes (P < 0.05). The expression of FABP4 in mix 3 (75% C16:0-25% C18:1cis-9) was substantially different from all other treatments aside from a similarly structured mix (50% C16:0-50% C18:1cis-9; P < 0.05). The SCD-1 was upregulated, while peroxisome proliferating-activated receptor gamma (PPARy) was downregulated in the fully saturated fatty acid mix, mix 5 (50% C16:0- 50% C18:0), compared with all other treatments (P < 0.05). All three mixes containing C18:2cis-9 exhibited a greater relative expression of sterol-regulatory element-binding protein (SREB) than all other mixes (P < 0.05). The supplementation of fatty acids at different ratios can affect molecular mechanisms and hypertrophic growth in differentiated bovine adipocytes. Further investigation of this type of fatty acid supplementation could impact the future understanding of hypertrophic growth in the bovine adipocyte and provide further insight into the alteration of fat deposition in cattle.

SLC25A22 as a Key Mitochondrial Transporter Against Ferroptosis by Producing Glutathione and Monounsaturated Fatty Acids.

Aims: Ferroptosis, a type of oxidative cell death driven by unlimited lipid peroxidation, is emerging as a target for cancer therapy. Although mitochondrial dysfunction may lead to ferroptosis, the underlying molecular mechanisms and metabolic pathways for ferroptosis are incompletely understood. Here, we identify solute carrier family 25 member 22 (SLC25A22), a mitochondrial glutamate transporter, as a driver of ferroptosis resistance in pancreatic ductal adenocarcinoma (PDAC) cells. Results: The downregulation of SLC25A22 expression was associated with increased sensitivity to ferroptosis, but not to apoptosis. Mechanistically, on the one hand, SLC25A22-dependent NAPDH synthesis blocks ferroptotic cell death in PDAC cells through mediating the production of glutathione (GSH), the most important hydrophilic antioxidant. On the other hand, SLC25A22 promotes the expression of stearoyl-CoA desaturase in PDAC cells in an AMP-activated protein kinase-dependent manner, resulting in the production of antiferroptotic monounsaturated fatty acids (MUFAs). The animal study further confirms that SLC25A22 inhibits ferroptosis-mediated tumor suppression. Innovation: SLC25A22 is a novel metabolic repressor of ferroptosis by producing GSH and MUFAs. Conclusion: These findings establish a previously unrecognized metabolic defense pathway to limit ferroptotic cell death in vitro and in vivo. Antioxid. Redox Signal. 39, 166-185.

Phenotypic variation in milk fatty acid composition and its association with stearoyl-CoA desaturase 1 (SCD1) gene polymorphisms in Gir cows.

Individual variation in milk fatty acid (FA) composition has been partially attributed to stearoyl-CoA desaturase 1 (SCD1) gene polymorphisms in taurine breeds, but much less is known for Zebu breeds. This study investigated the phenotypic variation in milk FA composition, and the influence of SCD1 variants on this trait and on milk fat desaturase indices (DI) in Gir cows. The functional impact of SCD1 variants was predicted using bioinformatics tools. Milk and blood samples were collected from 312 cows distributed in 10 herds from five states of Brazil. SCD1 variants were identified through target sequencing, and milk FA composition was determined by gas chromatography. Phenotypic variation in milk FA composition fell within the range reported for taurine breeds, with SCD18 index showing the lowest variation among the DI. Fourteen SCD1 variants were identified, six of which not previously described. Regarding the A293V polymorphism, all cows were homozygous for the C allele (coding for alanine), whereas all genotypes were detected for the second SNP affecting the 293 codon (G > A), with compelling evidence for functional effects. Significant associations (based on raw p-values) were found between this SNP and C12:0, cis-9, trans-11 CLA and short-chain FA, and between another SNP (rs523411937) and C15:0 and odd-chain linear FA. A new SNP on Chr26:21277069 was associated with trans-11 C18:1, cis-9, trans-11 CLA, C18:3 n-3 and n-3 FA. These findings indicate that SCD1 polymorphisms also contributes to the phenotypic variation in milk FA composition of Gir cows, with potential use in their breeding programmes.

Association between Stearoyl CoA Desaturase (SCD) Gene Polymorphisms and Milk Production in Holstein Cattle Breed

The SCD gene is a significant component of the leptin signaling pathway. The SCD gene has also been suggested as a candidate essential gene that can change the ratio of saturated to unsaturated fatty acids in milk and increase the amount of conjugated linoleic fatty acid, which is thought to have anti-cancer properties. The current research was carried out on Holstein cows to determine the association between SCD (Stearoyl-Coenzyme A Desaturase) gene polymorphism and total milk yield at 305 days (TMY305) and daily milk yield (DMY). The polymorphism in the SCD gene was identified using the PCR-RFLP technique and the SatI restriction enzyme for genotyping at SNP c.878T>C in the exon 5. The TT, TC, and CC genotype frequencies were 0.21, 0.50, and 0.29 respectively. While the allele frequencies of T and C were 0.46 and 0.54, respectively. According to the Chi-square test results, the SCD/c.878T>C distribution was in Hardy-Weinberg disequilibrium (P<0.05). Statistical analysis indicated a significant association between the SCD gene polymorphism and TMY305 (P<0.05). The TC genotypes showed a higher mean TMY305 compared to the TT and CC genotypes.

Lithium Chloride Promotes Endogenous Synthesis of CLA in Bovine Mammary Epithelial Cells.

Although conjugated linoleic acid (CLA) can promote human health, its content in milk is insufficient to have a significant impact. The majority of the CLA in milk is produced endogenously by the mammary gland. However, research on improving its content through nutrient-induced endogenous synthesis is relatively scarce. Previous research found that the key enzyme, stearoyl-CoA desaturase (SCD) for the synthesis of CLA, can be expressed more actively in bovine mammary epithelial cells (MAC-T) when lithium chloride (LiCl) is present. This study investigated whether LiCl can encourage CLA synthesis in MAC-T cells. The results showed that LiCl effectively increased SCD and proteasome α5 subunit (PSMA5) protein expression in MAC-T cells as well as the content of CLA and its endogenous synthesis index. LiCl enhanced the expression of proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), and its downstream enzymes acetyl CoA carboxylase (ACC), fatty acid synthase (FASN), lipoprotein lipase (LPL), and Perilipin 2 (PLIN2). The addition of LiCl significantly enhanced p-GSK-3β, β-catenin, p-β-catenin protein expression, hypoxia-inducible factor-1α (HIF-1α), and downregulation factor genes for mRNA expression (P < 0.05). These findings highlight that LiCl can increase the expression of SCD and PSMA5 by activating the transcription of HIF-1α, Wnt/β-catenin, and the SREBP1 signaling pathways to promote the conversion of trans-vaccenic acid (TVA) to the endogenous synthesis of CLA. This data suggests that the exogenous addition of nutrients can increase CLA content in milk through pertinent signaling pathways.

Biochemical and gene expression differences associated with higher fat deposition in Krškopolje pigs in comparison with lean hybrid pigs

Krškopolje pig is the only preserved local pig breed in Slovenia. Compared to lean pig genotypes, it is characterised by greater capacity for lipid deposition. The underlying mechanisms responsible for a greater fat deposition in this breed have not yet been investigated. Therefore, the main objective of the present study was to determine differences in gene expression and lipid metabolism between Krškopolje pigs and lean hybrid pigs reared in the same environmental conditions. Despite a greater fat deposition, activities of lipogenic enzymes were lower in Krškopolje than in lean hybrid pigs (i.e. malic enzyme and glucose-6-phosphate dehydrogenase displayed 2.6- and 2.0-fold lower activity measured on tissue postmortem, respectively). Krškopolje pigs had also lower polyunsaturated fatty acid (PUFA) and higher saturated (SFA) and monounsaturated fatty acids (MUFA) content than their lean-type peers. Consistent with a higher MUFA, overexpression of the stearoyl-CoA desaturase gene was determined in Krškopolje pigs compared to the lean hybrid pigs. In accordance with higher adiposity, Krškopolje pigs exhibited higher expression of genes involved in lipogenesis (ACACA, FASN), adipogenesis (PPARγ) and energy homeostasis (LEP) than lean hybrid pigs. Regarding the sex effect in Krškopolje pigs, females exhibited higher lipogenic enzyme activities than surgically castrated males, while no significant differences were observed for fat quantity and quality traits or gene expression. In conclusion, Krškopolje pigs are characterised by a higher fat deposition associated with higher SFA and MUFA content, a higher expression of genes involved in lipogenesis, and lower activity of lipogenic enzymes compared to lean-type hybrid pigs.

Scd knockout activates β-oxidation of fatty acids via accumulating stearic acid (18:0) and induces anorexia in zebrafish

Stearoyl-CoA desaturase (scd) is the rate-limiting enzyme for the biosynthesis of monounsaturated fatty acids (MUFA), and it plays a critical role in regulating hepatic lipogenesis and lipid oxidation. However, its role in teleosts remains unclear. In this study, we generated scd knockout zebrafish (scd-/-) to explore the role of Scd in regulating growth and metabolism in teleosts. The results showed that scd knockout reduces hepatic lipid deposition by down-regulating the expression of lipogenesis-related genes and up-regulating the expression of lipolysis-related genes. In addition, the knockout of scd suppressed food intake and reduced body weight. Further analysis confirmed that scd knockout suppressed the feeding behavior by decreasing expression of orexigenic peptide genes and increasing expression of anorexigenic peptide genes. The high-level stearic acid (18:0) feeding experiment results showed that the accumulation of 18:0 inhibited feeding behavior, reduced food intake, decreased body weight, and increased lipid β-oxidation, which was essentially consistent with the phenotypes of scd deficiency. Taken together, our results indicate that the knockout of scd inhibited the food intake through the accumulation of 18:0. This study preliminarily reveals the role of Scd in regulating food intake of teleosts, which provides theoretical basis for the functional study of Scd.

Abstract LB014: Targeting Stearoyl-coA desaturase (SCD) as a therapeutic strategy in STK11/KEAP1 co-mutant non-small cell lung cancer

Abstract Introduction: Non-small cell lung cancer (NSCLC) is a highly prevalent subtype of lung cancer. Recent findings in the field have improved the clinical outcomes for only a subset of patients who are responsive to immunotherapy or have targetable oncogenic drivers. We have previously showed that concomitant loss of Serine/Threonine Kinase 11 (STK11) and Kelch-like ECH Associated Protein1 (KEAP1) detected in up to 10% NSCLC cases, dramatically enhances cell proliferation and invasion in vitro and in vivo. Bulk RNA sequencing identified upregulation of genes involved in ferroptosis, which is an iron dependent form of programmed cell death, in STK11/KEAP1 double mutant models, nominating ferroptosis as a potential vulnerability in these tumors. However, the mechanism of ferroptosis evasion in this subset in not well understood. Methods: We performed an in vitro CRISPR screen in STK11/KEAP1 co-mutant, single mutant and wild type cell lines. To further characterize the role of ferroptosis regulators in STK11/KEAP1 co-mutant setting, we performed phospho-kinase arrays and RNA sequencing in STK11/KEAP1 cell lines followed by validation through western blotting. Additionally, we performed gene expression analysis in patient derived xenografts (PDX) models treated with the SCD inhibitor to further characterize the mechanisms by which SCD inhibition has synthetic lethal effects in STK11/KEAP1 co-mutant background. Results: CRISPR/Cas9 based genetic screening identified stearoyl-CoA desaturase (SCD), a gene involved in ferroptosis protection, as a potential therapeutic target in the STK11/KEAP1 double mutant tumors. We further demonstrate that SCD overexpression protects STK11/KEAP1 co-mutant NSCLCs from undergoing ferroptosis. Pharmacological inhibition of SCD significantly reduced viability of STK11/KEAP1 co-mutant NSCLCs and made the co-mutant cells sensitive to ferroptosis induction. Phospho-kinase array showed downregulation of JAK-STAT and AKT signaling, in STK11/KEAP1 co-mutant NSCLCs as compared to both STK11 and KEAP1 single mutant isogenic conditions. The downregulation of these pathways was confirmed by gene expression profiling. To further understand the role of SCD in regulating ferroptosis we are studying the effect of concurrent loss of STK11 and KEAP1 on SCD on lipid oxidizing capacity and ferroptosis in a comprehensive panel of NSCLC cell lines and testing whether ferroptosis protection due to SCD overexpression leads to enhanced tumorigenesis in this co-mutant subtype of NSCLC in vivo and in vitro. Conclusions: Our study demonstrates the biological differences between STK11/KEAP1 co-mutant NSCLC as compared to the single mutants or wildtype counterparts in a KRAS mutation agnostic manner. In this study, we further establish SCD as a potential therapeutic strategy in STK11/KEAP1 co-mutant NSCLCs. We also show that SCD-mediated ferroptosis evasion is linked to multiple oncogenic signaling pathways which could be associated with ferroptosis. In summary we define a new therapeutic approach to STK11/KEAP1 co-mutant NSCLC to improve survival outcomes for patients diagnosed with this devastating disease. Citation Format: Utsav Sen, Triparna Sen. Targeting Stearoyl-coA desaturase (SCD) as a therapeutic strategy in STK11/KEAP1 co-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB014.

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

MiR-3180 inhibits hepatocellular carcinoma growth and metastasis by targeting lipid synthesis and uptake

PurposeReprogrammed lipid metabolism is a hallmark of cancer that provides energy, materials, and signaling molecules for rapid cancer cell growth. Cancer cells acquire fatty acids primarily through de novo synthesis and uptake. Targeting altered lipid metabolic pathways is a promising anticancer strategy. However, their regulators have not been fully investigated, especially those targeting both synthesis and uptake.MethodsImmunohistochemistry was performed on samples from patients with hepatocellular carcinoma (HCC) to establish the correlation between miR-3180, stearoyl-CoA desaturase-1 (SCD1), and CD36 expression, quantified via qRT-PCR and western blotting. The correlation was analyzed using a luciferase reporter assay. Cell proliferation, migration, and invasion were analyzed using CCK-8, wound healing, and transwell assays, respectively. Oil Red O staining and flow cytometry were used to detect lipids. Triglycerides and cholesterol levels were analyzed using a reagent test kit. CY3-labeled oleic acid transport was analyzed using an oleic acid transport assay. Tumor growth and metastasis were detected in vivo in a xenograft mouse model.ResultsMiR-3180 suppressed de novo fatty acid synthesis and uptake by targeting the key lipid synthesis enzyme SCD1 and key lipid transporter CD36. MiR-3180 suppressed HCC cell proliferation, migration, and invasion in an SCD1- and CD36-dependent manner in vitro. The mouse model demonstrated that miR-3180 inhibits HCC tumor growth and metastasis by inhibiting SCD1- and CD36-mediated de novo fatty acid synthesis and uptake. MiR-3180 expression was downregulated in HCC tissues and negatively correlated with SCD1 and CD36 levels. Patients with high miR-3180 levels showed better prognosis than those with low levels.ConclusionsOur investigation indicates that miR-3180 is a critical regulator involved in de novo fatty acid synthesis and uptake, which inhibits HCC tumor growth and metastasis by suppressing SCD1 and CD36. Therefore, miR-3180 is a novel therapeutic target and prognostic indicator for patients with HCC.

Stearoyl-CoA desaturase 1 deficiency exacerbates palmitate-induced lipotoxicity by the formation of small lipid droplets in pancreatic β-cells

The accelerating accumulation of surplus lipids in the pancreas triggers structural and functional changes in type 2 diabetes-affected islets. Pancreatic β-cells exhibit a restricted capacity to store fat reservoirs in lipid droplets (LDs), which act as transient buffers to prevent lipotoxic stress. With the increasing incidence of obesity, growing interest has been seen in the intracellular regulation of LD metabolism for β-cell function. Stearoyl-CoA desaturase 1 (SCD1) is critical for producing unsaturated fatty acyl moieties for fluent storage into and out of LDs, likely affecting the overall rate of β-cell survival. We explored LD-associated composition and remodeling in SCD1-deprived INS-1E cells and in pancreatic islets in wildtype and SCD1−/− mice in the lipotoxic milieu. Deficiency in the enzymatic activity of SCD1 led to decrease in the size and number of LDs and the lower accumulation of neutral lipids. This occurred in parallel with a higher compactness and lipid order inside LDs, followed by changes in the saturation status and composition of fatty acids within core lipids and the phospholipid coat. The lipidome of LDs was enriched in 18:2n−6 and 20:4n−6 in β-cells and pancreatic islets. These rearrangements markedly contributed to differences in protein association with the LD surface. Our findings highlight an unexpected molecular mechanism by which SCD1 activity affects the morphology, composition and metabolism of LDs. We demonstrate that SCD1-dependent disturbances in LD enrichment can impact pancreatic β-cells and islet susceptibility to palmitate, which may have considerable diagnostic and methodological value for the characterization of LDs in human β-cells in type 2 diabetes patients.

Long noncoding RNAs with peptide-encoding potential identified in esophageal squamous cell carcinoma: KDM4A-AS1-encoded peptide weakens cancer cell viability and migratory capacity.

Currently, the knowledge of long noncoding RNA (lncRNA)-encoded peptides is quite lacking in esophageal squamous cell carcinoma (ESCC). In this study, we simultaneously identified six lncRNA open reading frames (ORFs) with peptide-coding abilities including lysine-specific demethylase 4A antisense RNA 1 (KDM4A-AS1) ORF by combining weighted gene co-expression network analysis (WGCNA) for ESCC clinical samples, ribosome footprints, ORF prediction, mass spectrometry (MS) identification, and western blotting. KDM4A-AS1 ORF-encoded peptide reduced ESCC cell viability and migratory ability. Co-immunoprecipitation and MS analysis revealed that KDM4A-AS1-encoded peptide specifically bound with 103 proteins in ESCC cells, and enrichment analysis suggested that peptide-bound proteins were related to fatty acid metabolism and redox process. Cell and molecular experiments demonstrated that KDM4A-AS1-encoded peptide inhibited stearoyl-CoA desaturase and fatty acid synthase expression, increased reactive oxygen species level, and reduced mitochondrial membrane potential in ESCC cells. In summary, multiple lncRNAs with translation potential were simultaneously identified by combining multiple approaches in ESCC, providing novel identificationstrategies for lncRNA-encoded peptides. Moreover, lncRNA KDM4A-AS1-encoded peptide weakened ESCC cell viability and migratory capacity and functioned in fatty acid metabolism and redox process.

HOXB9 a miR-122–5p regulated gene, suppressed the anticancer effects of brusatol by upregulating SCD1 expression in melanoma

Brusatol (Bru), a Chinese medicine Brucea javanica extract, has a variety of antitumour effects. However, its role and underlying mechanism in melanoma have not been fully elucidated. In this study, we found that brusatol inhibited melanoma cell proliferation and migration and promoted cell apoptosis in vitro, in addition to suppressing melanoma cell tumorigenesis in vivo. Further studies on the mechanism revealed that brusatol significantly downregulated the expression of stearoyl-CoA desaturase 1 (SCD1). Increased SCD1 expression could impair the antitumour effects of brusatol on melanoma cells. Subsequently, we found that HOXB9, an important transcription factor, was directly bound to the promoter of SCD1, facilitating its transcription. Overexpression of HOXB9 inhibited brusatol-induced SCD1 reduction and promoted cell survival. Furthermore, our results revealed that miR-122–5p was significantly increased in response to brusatol treatment and led to a decrease in HOXB9 in melanoma. Collectively, our data suggested that the miR-122–5p/HOXB9/SCD1 axis might play an important role in the antitumour effects of brusatol and that brusatol might have potential clinical implications in melanoma therapy.

A Comparative Study on the Carcass and Meat Chemical Composition, and Lipid-Metabolism-Related Gene Expression in Korean Hanwoo and Brindle Chikso Cattle.

The objective of this study was to elucidate the effect of cattle breed on carcass and meat chemical composition, fatty acid profiles, and lipid-metabolism-related genes. For this study, same-age Hanwoo and Chikso steers (n = 6 per breed) reared under identical conditions were used. Immediately after slaughter, muscle tissues were collected for analysis of mRNA expression. At 24 h post-mortem, the carcasses were assessed for carcass traits (marbling score, meat yield, etc.), and meat quality and fatty acid profiles in the longissimus lumborum (LL) and semimembranosus (SM) muscles. The results showed that no differences in the slaughter weight, dressing rate, back-fat thickness, trimmed fat, and total meat yield occurred between the two breeds (p > 0.05). However, Hanwoo cattle had a higher marbling score, intramuscular fat (IMF) content, and expression level of lipid-metabolism-related genes such as lipoprotein lipase, peroxisome proliferator-activated receptor gamma, and fatty acid binding protein 4, compared with Chikso (p < 0.05). Contrastingly, Chikso had a higher total unsaturated fatty acid content and expression level of stearoyl CoA desaturase 1 (p < 0.05). It may be said that the difference in the expression levels of lipid-metabolism-related genes could be the molecular factors underlying IMF deposition and fatty acid profile differences in the beef from the two breeds.