stearoyl-CoA Desaturase Research Articles

Metabolomics Reveals the Mechanism by Which Sodium Butyrate Promotes the Liver Pentose Phosphate Pathway and Fatty Acid Synthesis in Lactating Goats

This study aimed to explore the effects of sodium butyrate on liver metabolism in goats subjected to a high-concentrate diet. We randomly assigned twelve Saanen-lactating goats into two groups, one of which received a high-concentrate diet (concentrate: forage = 60:40, control group), while the other received the same basal diet supplemented with sodium butyrate (SB) (10 g/kg basal diet, SB group). Compared with the control diet, the SB diet considerably increased the milk fat percentage and content (p < 0.05), with an increase of 0.67% in the milk fat content of the SB group. By employing a global metabolomics approach based on ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS), we identified 6748 ions in ESI+ mode and 3573 ions in ESI− mode after liver isolation from both groups. A total of twenty-three metabolites, including phospholipids, fatty acids, and ribose phosphate, were found to be dysregulated according to a search against the human metabolome database (HMDB). Pathway analysis revealed activation of the pentose phosphate pathway, glycerophospholipid metabolism, and unsaturated fatty acid synthesis. The SB diet also modulated the expression of key lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and stearoyl-CoA desaturase (SCD-1), which are downstream targets of the transcription factor sterol regulatory element-binding proteins-1c (SREBP-1c), inducing a significant upregulation (p < 0.05). Furthermore, 6-phosphogluconate dehydrogenase (6PGDH) levels in the liver were elevated after the lactating goats were fed the SB diet (p < 0.05). Our study reveals that the SB diet may offer substantial benefits in enhancing the milk quality of subacute ruminal acidosis (SARA) goats. This is accomplished by augmenting the activity of the liver pentose phosphate pathway and the process of de novo fatty acid synthesis in lactating goats.

Cicer arietinum phytosome ameliorates hepatosteatosis via downregulation of fatty acid synthase and stearoyl-CoA desaturase 1 in rats

Abstract Background Hepatosteatosis is considered a universal problematic health due to bad lifestyle. Thereby, the current study evaluates the influence of the Cicer arietinum polyunsaturated fatty acids (CAP) and newly synthesized C. arietinum polyunsaturated fatty acids phytosome (CAPP) against non-alcoholic fatty liver disease (NAFLD) persuaded through a high-fat diet (HFD) in addition to tamoxifen (TAM) in male albino rats. Forty-eight rats were separated into eight groups (6 rats/group). Rats of the control group were administered distilled water for 45 consecutive days, while phosphatidyl choline (PC), CAP, and CAPP groups administered distilled water (15 days), afterward administered PC, CAP, and CAPP, respectively (500 mg/kg b.wt), orally for 30 days. All the previous groups fed normal diet for the 45 days, while NAFLD rats feed HFD for 45 days and receive TAM (200 mg/kg b.wt, i.p) daily for 15 days, followed by administration of vehicle, PC, CAP, and CAPP orally for another 30 days. Results Hepatosteatosis was appraised biochemically by significant increase in the concentrations of serum AST, ALT, γGT, LDH, ALP, total bilirubin, total lipid, triglycerides, fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD-1), and LDL-cholesterol, as well as hepatic total lipids and triglycerides. In addition, a significant decline in serum total protein, albumin, and HDL-cholesterol concentrations was observed in comparison with the control group. NAFLD induces oxidative stress by noteworthy increase in hepatic MDA, H2O2, and meaningful reduction in hepatic GSH, SOD, GST, GRD, and CAT levels as compared with the corresponding control group. Liver histological changes were noted in the NAFLD group as compared to the control. Interestingly, CAP and CAPP treatments modulate the abnormal effects of NAFLD in all the previous parameters. For the histological changes caused by NAFLD, the liver tissue appeared nearly normal after the treatment with CAP and CAPP. Conclusion CAP and CAPP administration may have a potential role in alleviating hepatosteatosis. This may relate to its downregulation against FAS, SCD-1, and oxidative stress.

STEM-08. LIPID SATURATION HOMEOSTASIS PRESENTS A TARGETABLE VULNERABILITY IN MYC-AMPLIFIED GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain cancer, originating from the cerebellum. Despite advancements in standard of care (SoC), MB remains fatal for 30% of patients. Tumor relapse, spinal metastasis and treatment resistance are the most prevalent in MYC-driven Group 3 MB (G3-MB). Patients surviving SoC are faced with life-long neurocognitive and neurodevelopmental deficits. These issues highlight the urgent need for improved treatment modalities. Reprogramming of cellular lipid metabolism is an emerging hallmark of cancer and may yield novel cancer-specific therapeutic options. Here we explore the lipidome of both G3-MB and its proposed cell of origin, human neural stem cells (hNSCs) by comparing untargeted lipidomics using Liquid-Chromatography-Mass Spectrometry (LC-MS). Comparative analyses revealed a differential abundance of distinct lipid species in G3-MB, with an overall reduced saturation level of fatty acids (FAs). These findings implicate the de novo lipid synthesis (DNL) pathway. We identified the enzymes involved in DNL to be essential for MB survival in our genome-wide CRISPR KO screen. Additionally, mRNA expression of the DNL enzymes increases at relapse in our SoC-adapted murine patient-derived xenograft (PDX) model. Pharmacological and genetic targeting of the DNL enzyme Stearoyl-CoA Desaturase 1 (SCD1) selectively targets G3-MB. Furthermore, small molecule treatment of SCD1 demonstrates efficacy against G3-MB PDX models in vivo. We identified SCD expression as a prognostic marker in Group 3 and 4 MB patients and identified possible pathways for MB treatment. Overall, these findings indicate that SCD1 is a potent target for the treatment of G3-MB.

DNAR-12. STEAROYL-COA DESATURASE REGULATES DNA DAMAGE REPAIR IN GBM BY MODULATING PARP1 ACTIVITY

Abstract Glioblastoma (GBM) is the most prevalent malignant brain cancer in adults, notorious for its aggressiveness and resistance to therapy. GBM patients commonly receive radiation therapy combined with temozolomide (TMZ), which engages tumor cells to promote lethal DNA damage and subsequent cytotoxicity. Active DNA repair mechanisms, particularly in a subset population of GBM stem-like cells (GSCs), drive therapeutic resistance, thus largely contributing to the bleak prognosis of GBM. Poly (ADP-ribose) polymerases (PARPs) are essential in various cellular processes, including DNA repair. We have previously reported that fatty acid desaturation mediated by Stearoyl-CoA desaturase 1 (SCD1) plays a cytoprotective role in GSCs. Inhibiting SCD prevents tumor initiation and inhibits DNA damage repair, hence sensitizing to radiation and TMZ. Yet, the mechanistic role of SCD in DNA damage regulation remained unknown. Here, we found that the expression of both human isoforms of SCD, SCD1, and SCD5, directly correlates with PARP protein levels and subcellular localization. Downregulating SCD1/5 in GSCs resulted in significantly lower levels of PARP1, coupled with increased DNA damage, as well as reduced DNA damage repair and chromosome assembly. Conversely, cells overexpressing SCD1/5 exhibited higher PARP1 expression and lower levels of basal DNA damage compared to control GSCs. Notably, SCD1/5 overexpression also led to increased resistance to TMZ. We show that SCD1/5 regulates PARP activity by controlling PARP1 subcellular localization. In addition to decreased total levels of PARP following SCD1/5 downregulation, we also found increased PARP1 self-PARylation. Using confocal microscopy, we show that when SCD1/5 is repressed, PARylated PARP translocates from the nucleus to the cytosol, rendering it unable to bind DNA and recruit DNA-repairing machinery. In conclusion, our study provides a direct link between fatty acid metabolism and PARP1-mediated DNA damage repair.

TMET-03. ONCOGENIC STAT3 PROMOTES TUMOR GROWTH VIA STIMULATION THE SCAP- AND SREBP-1-REGULATED LIPOGENIC PATHWAY

Abstract Augmented lipogenesis is a hallmark of cancer. In addition, signal transducer and activator of transcription 3 (STAT3) is aberrantly activated and associated with poor prognosis in multiple cancers. Whether oncogenic STAT3 has an intrinsic and causal link to lipogenesis in cancer remains unclear. Here, we show that inhibition of STAT3 significantly alters the lipid profile of tumor cells, including free fatty acids and derived membrane structural phospholipids (phosphatidic acid, phosphatidylinositol, phosphatidylserine and sphingomyelin), this change results in cell death which could be rescued by lipids (oleic acid and palmitoleic acid) supplementation, while suppressing the gene and protein expression of major mediators of the lipogenic pathway including sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-1, fatty acid synthase and stearoyl-CoA desaturase 1. Furthermore, we show that STAT3 binds the promoter of SCAP, SREBP-1a and SREBP-1c, to promote their transcription in tumor cells. Finally, targeting STAT3 in a xenograft mouse model blocked glioblastoma growth and lipogenic enzyme expression. Our study reveals a novel regulatory pathway of STAT3-SCAP/SREBP-1 involved in tumor growth in vitro and in vivo, connecting STAT3 signaling with SCAP- and SREBP-1-mediated lipogenesis.

ARMC5 selectively degrades SCAP-free SREBF1 and is essential for fatty acid desaturation in adipocytes

SREBF1 plays the central role in lipid metabolism. It has been known that full-length SREBF1 that did not associate with SCAP (SCAP-free SREBF1) is actively degraded, but its molecular mechanism and its biological meaning remain unclear. ARMC5-CUL3 complex was recently identified as E3 ubiquitin ligase of full-length SREBF. Although ARMC5 was involved in SREBF pathway in adrenocortical cells, the role of ARMC5 in adipocytes has not been investigated. In this study, adipocyte-specific Armc5 knockout mice were generated. In the white adipose tissue (WAT) of these mice, all the stearoyl-CoA desaturase (Scd) were drastically downregulated. Consistently, unsaturated fatty acids were decreased and saturated fatty acids were increased. The protein amount of full-length SREBF1 were increased, but ATAC-Seq peaks at the SREBF1-binding sites were markedly diminished around the Scd1 locus in the WAT of Armc5 knockout mice. Armc5-deficient 3T3-L1 adipocytes also exhibited downregulation of Scd. Mechanistically, disruption of Armc5 restored decreased full-length SREBF1 in CHO cells deficient for Scap. Overexpression of Scap inhibited ARMC5-mediated degradation of full-length SREBF1, and overexpression of Armc5 increased nuclear SREBF1/full-length SREBF1 ratio and SREBF1 transcriptional activity in the presence of exogenous SCAP. These results demonstrated that ARMC5 selectively removes SCAP-free SREBF1 and stimulates SCAP-mediated SREBF1 processing, hence is essential for fatty acid desaturation in vivo.

Stearoyl CoA desaturase inhibition can effectively induce apoptosis in bladder cancer stem cells

Bladder cancer stands as one of the most prevalent cancers worldwide. While our previous research confirmed the significant role of stearoyl-CoA desaturase (SCD) in bladder cancer, the underlying reasons for its abnormal overexpression remain largely unknown. Moreover, the distinct response to SCD inhibitors between cancer stem cells (CSCs) and adherent cultured cell lines lacks clear elucidation. Therefore, in this experiment, we aim to conduct an analysis and screening of the SCD transcription start site, further seeking critical transcription factors involved. Simultaneously, through experimental validation, we aim to explore the pivotal role of endoplasmic reticulum stress/unfolded protein response in drug sensitivity among cancer stem cells. Additionally, our RNA-seq and lipid metabolism analysis revealed the significant impact of nervonic acid on altering the proliferative capacity of bladder cancer cell lines.

Therapeutic Potential of Stearoyl-CoA Desaturase1 (SCD1) in Modulating the Effects of Fatty Acids on Osteoporosis.

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.

Intermittent cold stimulation acclimates broilers to acute cold stress by affecting cardiac lipid metabolism.

This study aimed to investigate whether intermittent cold stimulation can induce adaptation in broilers to acute cold stress (ACS) by regulating the lipid metabolism of hearts. CS0 were kept at normal rearing temperature, while CS3 and CS5 were exposed to 3°C for 3 and 5 hours, respectively, on alternate days lower than CS0 from 15d to 35d. On 50d, broilers in three groups were exposed to ACS at 10°C for 12 hours (Y12). The levels of corticosterone (CORT) and liothyronine (T3), mRNA and protein levels of heart AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway genes were assessed at 36d, 50d and Y12. At 36d, mRNA levels of AMPKα, acyl-CoA oxidase (ACO), mTOR, sterol-regulatory element binding protein (SREBP), stearoyl-coA desaturase (SCD), acetyl-coA carboxylase (ACC), fatty acid synthase (FAS) and protein level of peroxisome proliferators-activated receptor α (PPARα) in CS3 and CS5 were significantly lower than those in CS0 (p<0.05). At 50d, compared to CS0, mRNA levels of PPARα, carnitine palmitoyltransferase1 (CPT1), ACO, tuberous sclerosis complex (TSC), SREBP and SCD, as well as protein levels of p-AMPKα/AMPKα, PPARα and SREBP were significantly increased in CS5 (p<0.05). At Y12, the levels of T3 in CS3 and CS5 were significantly higher than those in CS0 (p<0.05), mRNA levels of CPT1, ACO, SREBP, SCD and protein levels of p-AMPKα/AMPKα, SREBP, and FAS were significantly higher in CS5 than in CS0 and CS3 (p<0.05). However, compared to 50d, at Y12, mRNA levels of AMPKα, CPT1 and ACO in CS3 and CS5 significantly decreased (p<0.05), while protein levels of p-AMPKα/AMPKα significantly increased (p<0.05). This study suggested that intermittent cold stimulation at 3°C lower than normal rearing temperature for 5h could help broilers adapt to the ACS by promoting heart lipid metabolism.

6-Gingerol Inhibits De Novo Lipogenesis by Targeting Stearoyl-CoA Desaturase to Alleviate Fructose-Induced Hepatic Steatosis.

Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), is a worldwide liver disease without definitive or widely used therapeutic drugs in clinical practice. In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)-proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis.

A diet high in glucose and deficient in dietary fibre causes fat accumulation in the liver without weight gain

This study investigated whether a standard calorie diet that is high in glucose and deficient in dietary fibre (described as HGD [high glucose diet]) induces hepatic fat accumulation in mice. We evaluated hepatic steatosis at 7 days and 14 days after the commencement of the HGD. Hepatic triglycerides and areas of oil droplets increased in the HGD group both at day 7 and day 14, whereas weight gain, weight of epididymal fat, and plasma levels of triglycerides were unaffected by HGD consumption. A microarray analysis of the livers revealed that the expression of lipogenesis-related genes was the most affected by HGD consumption. Furthermore, HGD consumption induced the expression of hepatic proteins of fatty acid synthetase, acetyl-CoA carboxylase alpha, and stearoyl-CoA desaturase 1, which are known to be involved in the synthesis of triglyceride. These results indicate that HGD consumption causes fat accumulation in the liver, with an increase in enzymes that are involved in de novo lipogenesis without an accompanying weight or obesity phenotype. Our new findings suggest that HGD consumption could serve as a breeding ground for liver steatosis.

Ovarian multi-omics analysis reveals key rate-limiting enzymes FASN, SCD5, FADS1, 3BHSD, and STAR as potential targets for regulating kidding traits in goats

The kidding traits of goats are an important index of production. However, the molecular regulatory mechanisms of kidding traits in goats have not been fully elucidated. This study aimed to investigate the molecular regulatory network of kidding traits in goats. Multi-omics revealed the enrichment of 10 signaling pathways, with fatty acid biosynthesis, biosynthesis of unsaturated fatty acids, and steroid hormone biosynthesis pathways being closely related to reproduction. Interestingly, the key rate-limiting enzymes, fatty acid synthase (FASN), stearoyl-CoA desaturase 5 (SCD5), fatty acid desaturase 1 (FADS1), 3β-hydroxysteroid dehydrogenase/isomerase (3BHSD), and steroidogenic acute regulatory protein (STAR) enriched in these pathways regulate changes in reproduction-related metabolites. In interference experiments, it was observed that suppressing these key rate-limiting enzymes inhibited the expression of CYP19A1, ESR2, and FSHR. Furthermore, interference inhibited granulosa cell proliferation, caused cell cycle arrest, and promoted apoptosis. Thus, these results suggest that the specific markers of nanny goats with multiple kids are the key rate-limiting enzymes FASN, SCD5, FADS1, 3BHSD, and STAR. These findings may greatly enhance the understanding of regulatory mechanisms that govern goat parturition.

A Plasmodium late liver stage arresting GAP provides superior protection in mice.

Liver-stage genetically attenuated malaria parasites (GAPs) are powerful immunogens that provide protection against sporozoite challenge. We previously generated two late liver-stage-arresting GAPs by deleting the stearoyl-CoA desaturase (Scd) or sporozoite conserved orthologous transcript 1 (Scot1) genes in Plasmodium berghei. Immunization with Scd or Scot1 GAP conferred complete protection against a sporozoite challenge. In a safety study, we observed rare breakthrough blood-stage infections in mice inoculated with high doses of sporozoites, indicating that both GAPs were incompletely attenuated. In this study, we generated a Scd/Scot1 GAP by dual gene deletion. This resulted in complete attenuation of the parasites in the liver and did not transition to blood-stage infection despite a high-dose sporozoite challenge. The Scd/Scot1 KO and WT GFP parasites were indistinguishable during blood, mosquito and early liver stage development. Moreover, Scd/Scot1 KO liver-stage schizonts exhibited an abnormal apicoplast biogenesis and nuclear division phenotype, failed to form hepatic merozoites, and exhibited late liver-stage arrest. Compared with early-arresting Speld KO immunization, late-stage liver-arresting Scd/Scot1 KO induces greater and broader CD8+ T-cell responses and elicits stage-transcending immunity that provides superior protection in C57BL/6 mice. These data prove that multiple gene deletions lead to complete attenuation of the parasite and support the development of late liver stage-arresting P. falciparum GAP.

An Investigation of Polymorphism on the FASN, SCD1, and SLC27A3 Genes in Sheep

Milk traits of sheep are affected by many environmental and genetic factors. These traits are quantitative traits and are determined by many genes. This study aimed to investigate polymorphisms of milk-related Fatty-acid synthase (FASN), Stearoyl-CoA desaturase (SCD1), and solute carrier 27A3 (SLC27A3) genes in cross-bred Hamdani sheep. Blood samples were collected from 100 healthy cross-bred Hamdani ewes from the jugular vein into K3-EDTA-containing tubes. Genomic DNA was extracted using a commercial DNA isolation kit. PCR products of FASN (275 bp), SCD1 (225 bp), SLC27A3-P1 (341 bp), and SLC27A3-P2 (319 bp) were subjected to restriction fragment length polymorphism (RFLP) analysis using SSil (AciI), Cfr13I, AluI, and Hpy188III the restriction enzyme, respectively. However, all gene regions were found to be monomorphic. In the study, only TT, AA, AA, and GG genotypes were detected for FASN, SCD1, SLC27A3-P1, and SLC27A3-P2, respectively. Allele and genotype frequencies were 1.00 for all genotypes and alleles. Although this study did not reveal favorable genotypes in FASN, SCD1, and SLC27A3 genes that can be used for milk traits, more comprehensive studies with larger sample sizes should be conducted to investigate polymorphisms in cross-bred Hamdani sheep.

(E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone, a Major Homoisoflavonoid, Attenuates Free Fatty Acid-Induced Hepatic Steatosis by Activating AMPK and PPARα Pathways in HepG2 Cells.

(E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HMC), a homoisoflavonoid isolated from Portulaca oleracea, has significant anti-adipogenesis potential; it regulates adipogenic transcription factors. However, whether HMC improves hepatic steatosis in hepatocytes remains vague. This study investigated whether HMC ameliorates hepatic steatosis in free fatty acid-treated human hepatocellular carcinoma (HepG2) cells, and if so, its mechanism of action was analyzed. Hepatic steatosis was induced by a free fatty acid mixture in HepG2 cells. Thereafter, different HMC concentrations (10, 30, and 50 µM) or fenofibrate (10 µM, a PPARα agonist, positive control) was treated in HepG2 cells. HMC markedly decreased lipid accumulation and triglyceride content in free fatty acid-treated HepG2 cell; it (10 and 50 μM) markedly upregulated protein expressions of pAMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. HMC (10 and 50 μM) markedly inhibited the expression of sterol regulatory element-binding protein-1c, fatty acid synthase, and stearoyl-coA desaturase 1, which are the enzymes involved in lipid synthesis. Furthermore, HMC (10 and 50 μM) markedly upregulated the protein expression of peroxisome proliferator-activated receptor alpha (PPARα) and enhanced the protein expressions of carnitine palmitoyl transferase 1 and acyl-CoA oxidase 1. HMC inhibits lipid accumulation and promotes fatty acid oxidation by AMPK and PPARα pathways in free fatty acid-treated HepG2 cells, thereby attenuating hepatic steatosis.

Transcriptome Analysis Reveals the Early Development in Subcutaneous Adipose Tissue of Laiwu Piglets.

Adipose tissue plays an important role in pig production efficiency. Studies have shown that postnatal development has a vital impact on adipose tissue; however, the mechanisms behind pig adipose tissue early-life programming remain unknown. In this study, we analyzed the transcriptomes of the subcutaneous adipose tissue (SAT) of 1-day and 21-day old Laiwu piglets. The results showed that the SAT of Laiwu piglets significantly increased from 1-day to 21-day, and transcriptome analysis showed that there were 2352 and 2596 differentially expressed genes (DEGs) between 1-day and 21-day SAT in male and female piglets, respectively. Expression of genes in glycolysis, gluconeogenesis, and glycogen metabolism such as pyruvate kinase M1/2 (PKM), phosphoenolpyruvate carboxy kinase 1 (PCK1) and amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) were significantly different between 1-day and 21-day SAT. Genes in lipid uptake, synthesis and lipolysis such as lipase E (LIPE), acetyl-CoA carboxylase alpha (ACACA), Stearoyl-CoA desaturase (SCD), and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were also differentially expressed. Functional analysis showed enrichment of DEGs in transcriptional regulation, protein metabolism and cellular signal transduction. The protein-protein interaction (PPI) networks of these DEGs were analyzed and potential hub genes in these pathways were identified, such as transcriptional factors forkhead box O4 (FOXO4), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein delta (CEBPD), signal kinases BUB1 mitotic checkpoint serine/threonine kinase (BUB1) and cyclin-dependent kinase 1 (CDK1), and proteostasis-related factors ubiquitin conjugating enzyme E2 C (UBE2C) and cathepsin D (CTSD). Moreover, we further analyzed the transcriptomes of SAT between genders and the results showed that there were 54 and 72 DEGs in 1-day and 21-day old SAT, respectively. Genes such as KDM5D and KDM6C showed gender-specific expression in 1-day and 21-day SAT. These results showed the significant changes in SAT between 1-day and 21-day in male and female Laiwu pigs, which would provide information to comprehensively understand the programming of adipose tissue early development and to regulate adipose tissue function.

Leonurine Inhibits Hepatic Lipid Synthesis to Ameliorate NAFLD via the ADRA1a/AMPK/SCD1 Axis.

Leonurine is a natural product unique to the Lamiaceae plant Leonurus japonicus Houtt., and it has attracted attention due to its anti-oxidative stress, anti-apoptosis, anti-fibrosis, and metabolic regulation properties. Also, it plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms, but its mechanism of action remains to be elucidated. Therefore, this study aims to preliminarily explore the mechanisms of action of leonurine in NAFLD. Mice were randomly divided into four groups: the normal control (NC) group, the Model (M) group, the leonurine treatment (LH) group, and the fenofibrate treatment (FB) group. The NAFLD model was induced by a high-fat high-sugar diet (HFHSD) for 12 weeks, and liver pathological changes and biochemical indices were observed after 12 weeks. Transcriptomic analysis results indicated that leonurine intervention reversed the high-fat high-sugar diet-induced changes in lipid metabolism-related genes such as stearoyl-CoA desaturase 1 (Scd1), Spermine Synthase (Sms), AP-1 Transcription Factor Subunit (Fos), Oxysterol Binding Protein Like 5 (Osbpl5), and FK506 binding protein 5 (Fkbp5) in liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results suggest that leonurine may exert its lipid-lowering effects through the AMP-activated protein kinase (AMPK) signaling pathway. Liver lipidomic analysis showed that leonurine could alter the abundance of lipid molecules related to fatty acyl (FAs) and glycerophospholipids (GPs) such as TxB3, carnitine C12-OH, carnitine C18:1-OH, and LPC (20:3/0:0). Molecular biology experiments and molecular docking techniques verified that leonurine might improve hepatic lipid metabolism through the alpha-1A adrenergic receptor (ADRA1a)/AMPK/SCD1 axis. In summary, the present study explored the mechanism by which leonurine ameliorated NAFLD by inhibiting hepatic lipid synthesis via the ADRA1a/AMPK/SCD1 axis.

Fatty acid profiles unveiled: gene expression in Yanbian yellow cattle adipose tissues offers new insights into lipid metabolism

Abstract. Objectives. The objectives of this study were twofold: to analyze the composition and content of fatty acids in various adipose tissues (including kidney, abdominal, subcutaneous, and omental) of Yanbian yellow cattle and to observe the morphology of adipocytes within these tissues and to assess the level of expression of specific genes – kinase insert domain receptor (KDR), apolipoprotein L domain containing 1 (APOLD1), stearoyl-CoA desaturase 1 (SCD1), secreted frizzled-related protein 4 (SFRP4), fatty-acid-binding protein 5 (FABP5), and sterol carrier protein-2 (SCP2) – in different adipose tissues (kidney, abdominal, posterior belly, ribeye, prothorax, striploin, upper brain, and neck) of Yanbian yellow cattle. Method. Castrated Yanbian yellow cattle, 24 months old, with identical genetic backgrounds and raised under the same breeding management conditions, were selected. The fatty acid composition and content were assessed using gas chromatography, while the size and diameter of adipocytes were analyzed via paraffin sectioning. The level of expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results. In total, 16 distinct fatty acids were identified in abdominal adipose tissue. Additionally, henicosanoic acid (C21:0) and behenic acid (C22:0) were detected exclusively in subcutaneous adipose tissue. Caprylic acid (C8:0) was found in both kidney and omental adipose tissues. The size of individual adipocytes in kidney adipose tissue was notably larger compared to the adipocytes in the other three regions (p&lt;0.05). Regarding gene expression, APOLD1 exhibits its highest expression in striploin adipose tissues (p&lt;0.05), while SCD1 shows its peak expression in prothorax adipose tissues (p&lt;0.05). Moreover, both FABP5 and SCP2 demonstrate their highest level of expression in prothorax adipose tissue (p&lt;0.05). Furthermore, the level of expression of KDR and SFRP4 across these seven adipose tissue regions exhibits significant differences (p&lt;0.05). Conclusion. In conclusion, Yanbian yellow cattle exhibit variations in both the composition and content of fatty acids across different adipose tissue depots, including the kidney, abdominal, subcutaneous, and omental regions. Moreover, adipocytes display distinct morphological differences across these tissue types. Furthermore, the level of expression of KDR, APOLD1, SCD1, SFRP4, FABP5, and SCP2 varies significantly among adipose tissues located in the kidney, abdominal, posterior belly, ribeye, prothorax, striploin, upper brain, and neck regions.

Jolkinolide B Ameliorates Liver Inflammation and Lipogenesis by Regulating JAK/STAT3 Pathway.

Hepatic dysregulation of lipid metabolism exacerbates inflammation and enhances the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). STAT3 has been linked to lipid metabolism and inflammation. Jolkinolide B (JB), derived from Euphorbia fischeriana, is known for its pharmacological anti-inflammatory and anti-tumor properties. Therefore, this study investigated whether JB affects MASLD prevention by regulating STAT3 signaling. JB attenuated steatosis and inflammatory responses in palmitic acid (PA)-treated hepatocytes. Additionally, JB treatment reduced the mRNA expression of de-novo lipogenic genes, such as acetyl-CoA carboxylase and stearoyl-CoA desaturase 1. Interestingly, JB-mediated reduction in inflammation and lipogenesis was dependent on STAT3 signaling. JB consistently modulated mitochondrial dysfunction and the mRNA expression of inflammatory cytokines by inhibiting PA-induced JAK/STAT3 activation. This study suggests that JB is a potential therapeutic agent to prevent major stages of MASLD through inhibition of JAK/STAT3 signaling in hepatocytes.

Aurantio‑obtusin regulates lipogenesis and ferroptosis of liver cancer cells through inhibiting SCD1 and sensitizing RSL3.

Ferroptosis, characterized by iron‑mediated non‑apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio‑obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti‑hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit‑8, EdU staining and migration assays were employed to assess the anti‑liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl‑CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element‑binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.