stearoyl-CoA Desaturase Activity Research Articles

Abstract PO1-13-08: Comparative analysis of stearoyl-CoA desaturase 1 expression and activity index in model cell lines of breast cancer subclasses

Abstract Introduction Due to the unique conditions of the tumor microenvironment, such as hypoxia, poor angiogenesis, and mitochondrial dysfunction, cancer cells face challenges in obtaining nutrients and energy supply. However, monounsaturated fatty acids have been identified as preferred substrates for energy generation and maintenance of cellular structures in cancer cells. These fatty acids can be obtained through de novo fatty acid synthesis. Stearoyl-CoA desaturase 1 (SCD1) is the primary enzyme involved in the biosynthesis of monounsaturated fatty acids from saturated fatty acids and is known to be upregulated in various malignancies, including breast cancer. This study aimed to assess the expression and activity index of SCD1 in well-characterized MCF-7, SK-BR3, and MDA-MB231 breast cancer cell lines, representing luminal A/B, HER2-enriched, and triple-negative subtypes, respectively. Methods The breast cancer cell lines were cultured in RPMI-1640 medium with 10% fetal bovine serum at 37°C, 5% CO2, and 95% humidity for 72 hours. After harvesting the cells, SCD1 expression was analyzed using real-time quantitative PCR, and the activity index was determined by measuring the ratio of monounsaturated fatty acids to saturated fatty acids using capillary gas-liquid chromatography. Results MCF-7 cell line showed a significantly higher SCD1 expression compared to MDA-MB231 (250-fold, p< 0.0001) and SK-BR3 (83-fold, p< 0.0001) cell lines. The activity index of SCD1 was significantly higher in both MCF-7 and MDA-MB231 cell lines with fold changes of 2.6 and 2.5, respectively, compared to SK-BR3 cell line (p=0.004 for both). Conclusion Cell model assays demonstrated that the luminal A/B and triple-negative subtypes showed a higher capacity to convert saturated fatty acids to monounsaturated fatty acids through SCD1 enzyme activity, indicating a different lipid metabolism profile in the HER2-enriched subtype. These new findings reveal differences in SCD1 expression and activity among breast cancer subclasses. They highlight vulnerabilities in metabolism and identify potential therapeutic targets with clinical implications for managing breast cancer. Citation Format: Hamid-Reza Feizi, Amir Mehdizadeh, Zohreh Sanaat, Khadijeh Abbasi, Frank Gieseler, Masoud Darabi. Comparative analysis of stearoyl-CoA desaturase 1 expression and activity index in model cell lines of breast cancer subclasses [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-08.

Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control.

To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c=7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD116=palmitoleic acid/palmitic acid and SCD118=oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated. Three clusters were identified: CL1 (ADIPO-IR=4.9±2.4 and WC=96±7cm, mean±SD), CL2 (ADIPO-IR=6.5±2.5 and WC=114±7cm), and CL3 (ADIPO-IR=15.0±4.7 and WC=107±8cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p<0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p<0.005). High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. ID NCT00700856 https://clinicaltrials.gov.

Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression

Overnutrition and genetic predisposition are major risk factors for various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) plays a key role in these conditions by synthesizing unsaturated fatty acids (FAs), thereby promoting fat storage and alleviating lipotoxicity. Expression of SCD1 is influenced by various saturated and cis-unsaturated FAs, but the possible role of dietary trans FAs (TFAs) and SCD1 promoter polymorphisms in its regulations has not been addressed. Therefore, we aimed to investigate the impact of the two main TFAs, vaccenate and elaidate, and four common promoter polymorphisms (rs1054411, rs670213, rs2275657, rs2275656) on SCD1 expression in HEK293T and HepG2 cell cultures using luciferase reporter assay, qPCR and immunoblotting. We found that SCD1 protein and mRNA levels as well as SCD1 promoter activity are markedly elevated by elaidate, but not altered by vaccenate. The promoter polymorphisms did not affect the basal transcriptional activity of SCD1. However, the minor allele of rs1054411 increased SCD1 expression in the presence of various FAs. Moreover, this variant was predicted in silico and verified in vitro to reduce the binding of ETS1 transcription factor to SCD1 promoter. Although we could not confirm an association with type 2 diabetes mellitus, the FA-dependent and ETS1-mediated effect of rs1054411 polymorphism deserves further investigation as it may modulate the development of lipid metabolism-related conditions.

SCD1-related epigenetic modifications affect hormone-sensitive lipase (Lipe) gene expression in cardiomyocytes

Stearoyl-CoA desaturase 1 (SCD1) is an enzyme that is involved in the regulation of lipolysis in the heart. SCD1 also affects epigenetic mechanisms, such as DNA and histone modifications, in various tissues. Both epigenetic modifications and changes in lipid metabolism are involved in the heart's response to hypoxia. The present study tested the hypothesis that SCD1 and epigenetic modifications interact to control lipolysis in cardiomyocytes under normoxic and hypoxic conditions. We found that the inhibition of SCD1 activity and loss of SCD1 expression reduced global DNA methylation levels, DNA methyltransferase (DNMT) activity, and DNMT1 expression in HL-1 cardiomyocytes and the mouse heart. We also found that the inhibition of adipose triglyceride lipase is involved in the control of global DNA methylation levels in cardiomyocytes in an SCD1-independent manner. Additionally, SCD1 inhibition reduced expression of the hormone-sensitive lipase (Lipe) gene through an increase in methylation of the Lipe gene promoter. Under hypoxic conditions, SCD1 inhibition abolished hypoxia-inducible transcription factor 1α, likely through decreases in histone deacetylase, protein kinase A, and abhydrolase domain containing 5 protein levels, leading to the attenuation of DNA hypomethylation by DNMT1. Hypoxia led to demethylation of the Lipe promoter in cardiomyocytes with SCD1 inhibition, which increased Lipe expression. These results indicate that SCD1 is involved in the control of epigenetic mechanisms in the heart and may affect Lipe expression through changes in methylation in its promoter region. Therefore, SCD1 may be considered a key player in the epigenetic response to normoxia and hypoxia in cardiomyocytes.

Stearoyl-CoA desaturase 1 inhibition impairs triacylglycerol accumulation and lipid droplet formation in colorectal cancer cells.

Increases in fatty acid (FA) biosynthesis meet the higher lipid demand by intensely proliferating cancer cells and promoting their progression. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme in FA biosynthesis, converting saturated FA (SFA) into monounsaturated FA (MUFA). Increases in the MUFA/SFA ratio and SCD1 expression have been observed in cancers of various origins and correlate with their aggressiveness. However, much is still unknown about the SCD1-dependent molecular mechanisms that promote specific changes in metabolic pathways of cancer cells. The present study investigated the involvement of SCD1 in shaping glucose and lipid metabolism in colorectal cancer (CRC) cells. Excess FAs that derive from de novo lipogenesis are stored in organelles, called lipid droplets (LDs), mainly in the form of triacylglycerol (TAG) and cholesteryl esters. LD accumulation is associated with key features of cancer development and progression. Consistent with our findings, the pharmacological inhibition of SCD1 activity affects CRC cell viability and impairs TAG accumulation and LD formation in these cells through the activation of lipolytic and lipophagic pathways. We showed that SCD1 suppression affects crucial lipogenic processes that promote lipid accumulation in CRC cells but in a sterol regulatory element-binding protein 1-independent manner. We propose that adenosine monophosphate-activated protein kinase contributes to these changes through the activation of lipolysis and inhibition of TAG synthesis. We also provide evidence of the involvement of SCD1 in the regulation of glucose uptake and utilization in CRC cells. These findings underscore the importance of SCD1 in regulating cellular processes that promote cancer development and progression.

Free ferrous ions sustain activity of mammalian stearoyl-CoA desaturase-1

Mammalian stearoyl-CoA desaturase-1 (SCD1) introduces a double-bond to a saturated long-chain fatty acid in a reaction catalyzed by a diiron center. The diiron center is well-coordinated by conserved histidine residues and is thought to remain with the enzyme. However, we find here that SCD1 progressively loses its activity during catalysis and becomes fully inactive after about nine turnovers. Further studies show that the inactivation of SCD1 is due to the loss of an iron (Fe) ion in the diiron center and that the addition of free ferrous ions (Fe2+) sustains the enzymatic activity. Using SCD1 labeled with Fe isotope, we further show that free Fe2+ is incorporated into the diiron center only during catalysis. We also discover that the diiron center in SCD1 has prominent electron paramagnetic resonance signals in its diferric state, indicative of distinct coupling between the two ferric ions. These results reveal that the diiron center in SCD1 is structurally dynamic during catalysis and that labile Fe2+ in cells could regulate SCD1 activity and hence lipid metabolism.

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.

Role of Stearoyl-CoA Desaturase 1 in Cardiovascular Physiology.

Stearoyl-CoA desaturase is a rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Monounsaturated fatty acids limit the toxicity of exogenous saturated fats. Studies have shown that stearoyl-CoA desaturase 1 is involved in the remodeling of cardiac metabolism. The loss of stearoyl-CoA desaturase 1 reduces fatty acid oxidation and increases glucose oxidation in the heart. Such a change is protective under conditions of a high-fat diet, which reduces reactive oxygen species-generating β-oxidation. In contrast, stearoyl-CoA desaturase 1 deficiency predisposes individuals to atherosclerosis under conditions of hyperlipidemia but protects against apnea-induced atherosclerosis. Stearoyl-CoA desaturase 1 deficiency also impairs angiogenesis after myocardial infarction. Clinical data show a positive correlation between blood stearoyl-CoA Δ-9 desaturation rates and cardiovascular disease and mortality. Moreover, stearoyl-CoA desaturase inhibition is considered an attractive intervention in some obesity-associated pathologies, and the importance of stearoyl-CoA desaturase in the cardiovascular system might be a limitation for developing such therapy. This review discusses the role of stearoyl-CoA desaturase 1 in the regulation of cardiovascular homeostasis and the development of heart disease and presents markers of systemic stearoyl-CoA desaturase activity and their predictive potential in the diagnosis of cardiovascular disorders.

Abstract B039: Adipocyte regulation of ER stress and mTOR signaling in bone-metastatic PCa: The role of stearoyl-CoA desaturase

Abstract Bone metastatic disease is correlated with increased morbidity and mortality in prostate cancer (PCa) patients. Current treatments for bone-metastatic PCa are palliative, and new targets for therapy are desperately needed for this presently incurable disease. Various studies have determined that the supportive nature of the bone marrow (BM) niche and crosstalk between the bone-resident cells and the tumor lead to increased tumor cell survival and escape from therapy. Specifically, studies from our lab highlighted the critical role of bone marrow adipose tissue and its expansion due to obesity or age in PCa progression and chemoresistance in bone. Bone marrow adipocytes are metabolically active cells that, through secretion of lipids and adipokines, have the potential to affect the neighboring cells, including the tumor cells that have disseminated into the BM niche. We have shown previously that interaction with marrow adipocytes promotes lipid uptake by PCa cells, modulates their metabolic phenotype, and activates pro-survival signaling and ER/oxidative stress pathways; however, the molecular mechanisms behind the tumor-promoting effects of adipocytes are not understood. The main objective of this study was to investigate the molecular mechanisms underlying lipid-induced stress during tumor cell-adipocyte crosstalk and its functional relationship to tumor growth and progression in bone. Our preliminary data showed that adipocyte-tumor cell crosstalk increases lipid peroxidation in PCa cells, which coincides with augmented expression of ER stress markers and activation of mTOR signaling. We also observed that PCa cells under adipocyte exposure had augmented gene expression of stearoyl-CoA desaturase (SCD), an ER-resident enzyme responsible for the conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA). We, therefore, hypothesized that SCD is a metabolic regulator that protects metastatic PCa cells against lipid-induced toxicity and ER stress and promotes tumor survival via activation of mTOR signaling. Here, we show that the inhibition of mTORC1 by Everolimus (EVO) decreases the gene expression of ER stress markers in PCa cells exposed to adipocytes. We also demonstrate that adipocyte-mediated induction of ER stress coincides with an increase in active mTOR signaling in PCa cells, indicating possible bidirectional crosstalk between ER stress and mTOR pathways. Notably, inhibition of SCD in PCa cells grown in Transwell co-culture with adipocytes by either siRNA or the small molecule inhibitor CAY10566 leads to reduced mTOR signaling and an increase in lipid peroxidation in PCa cells. SCD inhibition also increases the gene and protein expression of ER stress markers, specifically XBP1 (S) and ATF4, suggesting apoptosis induction. Collectively, our results place SCD as a mediator of ER stress-mTOR crosstalk and a promoter of tumor survival and suggest that targeting SCD activity might be a viable approach to rewire tumor metabolism, and inhibit metastatic progression in bone and sensitize PCa tumors to therapy. Citation Format: Alexis Wilson, Mackenzie Herroon, Shane Mecca, Laimar Garmo, Izabela Podgorski. Adipocyte regulation of ER stress and mTOR signaling in bone-metastatic PCa: The role of stearoyl-CoA desaturase [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B039.

Pretreatment of human retinal pigment epithelial cells with sterculic acid forestalls fenretinide-induced apoptosis

The ratio of saturated to monounsaturated fatty acids, thought to play a critical role in many cellular functions, is regulated by stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. Previously, we observed a decrease in both SCD protein and enzymatic activity in apoptosis induced by fenretinide, a synthetic analog of retinoic acid, in the human retinal pigment epithelial (RPE) cell line ARPE-19. Here, we investigated the effect of pretreating ARPE-19 with sterculic acid, a cyclopropenoic fatty acid inhibitor of SCD, on preventing fenretinide-induced apoptosis, given the role of SCD in cell proliferation and apoptosis. We show that sterculic acid pretreatment prevents the effects of fenretinide-induced apoptosis shown by changes in cell morphology, viability, and caspase-3 activation. Analysis of endoplasmic reticulum (ER)-associated proteins shows that sterculic acid pretreatment reduced the fenretinide-induced upregulation of heme oxygenase-1, ATF3 and GADD153 expression that are in response to reactive oxygen species (ROS) generation. Sterculic acid is as effective as allopurinol in inhibition of xanthine oxidase (XDH), and this may play a role in reducing the potential role of XDH in fenretinide-induced ROS generation. Sterculic acid pretreatment also results in a reduction in SOD2 mRNA expression. Dihydroceramide accumulation, compared to ceramide, and ROS generation indicate that a ceramide-independent pathway mediates fenretinide-induced apoptosis, and ROS mediation is borne out by activation of the NF-κBp50 and NF-κBp65 downstream signaling cascade. Its prevention by sterculic acid pretreatment further indicates the latter’s antioxidant/anti-inflammatory effect. Taken together, our results suggest that sterculic acid pretreatment can mitigate ROS-mediated fenretinide-induced apoptosis. Thus, sterculic acid may serve as a potential antioxidant and therapeutic agent. These effects may be independent of its effects on SCD activity.

Dietary isoleucine affects muscle fatty acid and amino acid profiles through regulating lipid metabolism and autophagy in hybrid catfish (Pelteobagrus vachelli ♀× Leiocassis longirostris ♂).

The present study explored the impacts of Ile on muscle fatty acid and amino acid profiles, lipid metabolism, and autophagy in hybrid catfish. Seven isonitrogenous (387.8g/kg protein) semi-purified diets were formulated to contain 5.0 (control), 7.5, 10.0, 12.5, 15.0, 17.5, and 20.0g Ile/kg diet respectively. The fish (initial weight of 33.11±0.09g) were randomly assigned to 7 groups for a 56-day trial. Each group has 3 replicates with 30 fish per replicate, fed at 08:00 and 18:00 each day. Results showed that muscle protein and lipid, C14:0, C18:0, C22:0, C14:1, C18:1n-9, polyunsaturated fatty acid (PUFA), Arg, Ile, Ala, Cys, Gly, Tyr, essential amino acid (EAA), and total amino acid (TAA) contents and flavor amino acid (FAA)/TAA in muscle had positive linear and/or quadratic responses to dietary Ile levels (P<0.05). Fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL) activities had positive linear and/or quadratic responses, but carnitine palmitoyl transferase 1 (CPT1) activity had a negative response with increasing dietary Ile levels (P<0.05). The mRNA expressions of FAS, SCD, ACC, LPL, fatty acid binding protein 4 (FABP4), FATP1, sterol response element-binding protein 1c (SREBP-1c), sequestosome 1 (SQSTM1), and adenosine 5'-monophosphate-activated protein kinase (AMPK) had positive linear and/or quadratic responses to dietary Ile levels (P<0.05). The mRNA expressions of hormone-sensitive lipase (HSL), CPT1, peroxisome proliferator-activated receptor α (PPARα), PPARγ, uncoordinated 51-like kinase 1 (ULK1), beclin1 (Becn1), autophagy-related protein 9α (Atg9α), Atg4b, Atg7, autophagy marker light chain 3B (LC3B), and SQSTM1 in muscle had negative linear and/or quadratic responses to dietary Ile levels (P<0.05). The p-AMPK and ULK1 protein levels, and p-AMPK/AMPK were decreased by 12.5g Ile/kg in the diet (P<0.05). Finally, SQSTM1 protein level had the opposite effect (P<0.05). The above results indicate that dietary Ile improves fish muscle fatty acid and amino acid profiles potentially via respectively regulating lipid metabolism and autophagy. The Ile requirement of hybrid catfish (33 to 72g) were estimated to be 12.63, 13.77, 13.75, 11.45, 10.50, 12.53 and 12.21g/kg diet based on the regression analysis of protein, lipid, SFA, PUFA, FAA, EAA, and TAA muscle contents, respectively.

TMET-02. THERAPEUTIC EFFICACY OF A NOVEL BRAIN PENETRANT SCD INHIBITOR ON BREAST CANCER BRAIN METASTASES

Abstract Brain metastases are a significant therapeutic challenge and are associated with high morbidity and mortality. Recent evidence suggests that brain metastases have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain fatty acids into monounsaturated fatty acids, is often upregulated in breast cancer brain metastasis (BCBM) and is considered a promising therapeutic target. However, the lack of brain penetrant SCD inhibitors limited their use in patients. This study aimed to investigate the therapeutic efficacy of a clinical-stage brain penetrant inhibitor of SCD to treat BCBM. We found that pharmacologic inhibition of SCD in multiple breast cancer cell lines induced significant cytotoxicity, mainly by apoptosis. Gas chromatography/mass spectrometry confirmed that the fatty acid desaturation index, which measures SCD activity, was significantly lower after treatment. SCD inhibition triggered endoplasmic reticulum (ER) stress and increased DNA damage due to a higher production of reactive oxygen species. Further, SCD inhibition decreased DNA damage repair by inhibiting homology-directed repair in vitro and in a mouse model of breast cancer. Notably, inhibition of SCD led to a significant decrease in tumor growth in a subcutaneous mouse model of breast cancer and a significant increase in overall survival in a BCBM mouse model. Cytotoxicity was enhanced when this SCD inhibitor was combined with either a DNA damage-inducing agent (temozolomide or radiation) or with a PARP inhibitor (Niraparib). Finally, we observed that combination therapy of SCD inhibition and Niraparib significantly increased overall survival in a BCBM mouse model. Our results suggest that inhibition of SCD alone or in combination with a PARP inhibitor is a promising therapeutic strategy to treat BCBM.

Mitochondrial dysfunction: The pathological link between psoriasis and insulin resistance?

Psoriasis is strongly associated with insulin resistance (IR). Lipid profile disturbances and upregulation of enzymes crucial for fatty acid oxidation have been reported in patients with psoriasis. Mitochondrial ß-oxidation is altered in patients with IR. Common mitochondrial dysfunction may be involved in the origin of both diseases. This study aimed to evaluate mitochondrial ß-oxidation, intermediary metabolism, and mitochondrial content in psoriatic patients with or without IR and compare them to healthy controls. The participants were divided into three groups: (1) psoriasis and IR (n=26); (2) psoriasis without IR (n=17); and (3) healthy controls (n=17). Quantification of amino acids and acylcarnitines (AC) by tandem mass spectrometry, determination of urinary organic acids by gas chromatography/mass spectrometry (GC/MS), and mitochondrial DNA quantification were performed in all groups. When comparisons were made between the two psoriatic groups, no differences were found between: C5DC + C6OH, C16:1, Met/Leu, Met/Phe, C16:1/C16, and C5DC + C6OH/C4DC + C5OH ratios. Nine analytes were different: phenylalanine, Cit/Phe, and Cit/Tyr ratios, C0, C3, C5, C6DC, C16, and C18:1OH. There were no correlations between psoriasis area and severity index (PASI), body mass index (BMI) and duration of disease with ACs. A higher proportion of patients with psoriasis showed increased urine levels of uric acid and hippuric acid (p=0.01). The mtDNA content was significantly higher in cases than in controls, with no differences between IR and non-IR psoriatic patients. Psoriasis patients with and without IR have a different acylcarnitine profile reflecting impaired ß-oxidation. A distinctive profile of acylcarnitines suggests an involvement of mitochondrial function associated with an increase in stearoyl CoA desaturase (SCD) activity in psoriatic patients with and without IR.

Stearoyl-CoA Desaturase Regulates Angiogenesis and Energy Metabolism in Ischemic Cardiomyocytes.

New blood vessel formation is a key component of the cardiac repair process after myocardial infarction (MI). Hypoxia following MI is a major driver of angiogenesis in the myocardium. Hypoxia-inducible factor 1α (HIF1α) is the key regulator of proangiogenic signaling. The present study found that stearoyl-CoA desaturase (SCD) significantly contributed to the induction of angiogenesis in the hypoxic myocardium independently of HIF1α expression. The pharmacological inhibition of SCD activity in HL-1 cardiomyocytes and SCD knockout in an animal model disturbed the expression and secretion of proangiogenic factors including vascular endothelial growth factor-A, proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1, and Rantes), metalloproteinase-9, and platelet-derived growth factor in ischemic cardiomyocytes. These disturbances affected the proangiogenic potential of ischemic cardiomyocytes after SCD depletion. Together with the most abundant SCD1 isoform, the heart-specific SCD4 isoform emerged as an important regulator of new blood vessel formation in the murine post-MI myocardium. We also provide evidence that SCD shapes energy metabolism of the ischemic heart by maintaining the shift from fatty acids to glucose as the substrate that is used for adenosine triphosphate production. Furthermore, we propose that the regulation of the proangiogenic properties of hypoxic cardiomyocytes by key modulators of metabolic signaling such as adenosine monophosphate kinase, protein kinase B (AKT), and peroxisome-proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor α depends on SCD to some extent. Thus, our results reveal a novel mechanism that links SCD to cardiac repair processes after MI.

Effects of sugar-sweetened soda on plasma saturated and monounsaturated fatty acids in individuals with obesity: A randomized study.

BackgroundHigh carbohydrate, i.e., sugars, intake potentially drives the liver into a lipogenic state leading to elevated plasma fatty acids. Excessive intake of saturated fat and sugar-sweetened soda induces liver fat accumulation, but studying the effect of high intake from sugar-sweetened soda on the de novo lipogenesis (DNL) fatty acids in long-term randomized trials is lacking.ObjectiveTo study the effect of consuming 1 L/day of sugar-sweetened soda, semi-skimmed milk (milk), aspartame-sweetened soda or water over 24 weeks on DNL-derived fatty acids (i.e., palmitate (primary outcome) and other saturated and monounsaturated fatty acids), and markers of stearoyl-CoA desaturase activity (SCD1) in plasma phospholipids (PL), cholesteryl esters (CE), and triglycerides (TG).Design and methodsA randomized parallel study was conducted simultaneously at Aarhus University Hospital and Copenhagen University, Denmark, including (n = 41) individuals aged 20–50 years, with BMI of 26–40 kg/m2, and without diabetes. The groups consisted of 9 individuals in the sugar-sweetened soda, 10 in the milk, 11 in the aspartame-sweetened soda, and 11 in the water. The change at 24 weeks was assessed and compared across the groups using ANCOVA and mixed-effects models. Correlations of fatty acid changes with liver fat accumulation (magnetic resonance imaging) were explored.ResultsAfter 24 weeks, the groups differed in palmitate proportions in PL, oleate in CE and PL, and palmitoleate and SCD1 in all fractions (p < 0.05). Compared with water, the relative proportion of palmitate in PL increased by approximately 1% during both sugar-sweetened soda (p = 0.011) and milk (p = 0.006), whereas oleate and palmitoleate increased only during sugar-sweetened soda (CE 2.77%, p < 0.001; PL 1.51%, p = 0.002 and CE 1.46%, PL 0.24%, TG 1.31%, all p < 0.001, respectively). Liver fat accumulation correlated consistently with changes in palmitoleate, whereas correlations with palmitate and oleate were inconsistent across lipid fractions.ConclusionsAlthough both sugar-sweetened soda and milk increased palmitate in PL, only excess intake of sugar-sweetened soda increased palmitoleate in all lipid fractions and correlated with liver fat. In contrast, isocaloric milk intake did not increase plasma monounsaturated fatty acids.Clinical trial registration[https://clinicaltrials.gov/ct2/show/NCT00777647], identifier [NCT00777647].

De novo lipogenesis mediates beneficial effects of isoenergetic dietary interventions on fatty liver: Insights from the MEDEA randomized clinical trial

Background and Aims : Fatty liver (FL) is a consequence of the imbalance between hepatic lipid storage, disposal, and partitioning. A Multifactorial-diet high in fiber, monounsaturated fatty acids (MUFA), n-6 and n-3 polyunsaturated fatty acids, polyphenols, and vitamins compared with a MUFA rich-diet, reduces FL in people with type 2 diabetes (T2D) by 40%. We evaluated whether dietary effects on LF were mediated by changes in hepatic De Novo Lipogenesis (DNL), stearoyl-CoA desaturase (SCD1) activity, or β-oxidation.

Elevated stearoyl-CoA desaturase 1 activity is associated with alcohol-associated liver disease.

Chronic binge drinking induces hepatic lipid accumulation, but only certain individuals develop alcohol-associated liver disease (ALD). Specific patterns of lipid accumulation are thought to be associated with ALD, but this has not been comprehensively investigated to date. We analyzed plasma fatty acid levels, quantified by gas chromatography-mass spectrometry, in a sample of patients with alcohol use disorder (AUD). Given that elevation in serum alanine transaminase (ALT) levels are strongly associated with ALD, patients were stratified into two groups based on ALT levels: an ALD group (ALT >40 IU/L) and a non-ALD group (ALT ≤40 IU/L). There was a shift toward greater concentrations of monounsaturated fatty acids in the ALD group compared to the non-ALD group. Stearoyl-CoA desaturase (SCD1) activity in the ALD group was then estimated as the ratio of palmitoleic acid (16:1) to palmitic acid (16:0). SCD1 activity was greater in the ALD than the non-ALD group. A series of linear regression models demonstrated that SCD1 activity mediated the association between binge drinking and ALD. These findings provide initial evidence that SCD1 activity may be associated with ALD. If validated prospectively, elevated SCD1 activity could potentially be used as a biomarker to identify individuals at high risk for developing ALD.

Stearoyl-CoA desaturase 1 as a therapeutic target for cancer: a focus on hepatocellular carcinoma.

One of the main characteristics of cancer cells is the alteration in lipid composition, which is associated with a significant monounsaturated fatty acids (MUFAs) enrichment. In addition to their structural functions in newly synthesized membranes in proliferating cancer cells, these fatty acids are involved in tumorigenic signaling. Increased expression and activity of stearoyl CoA desaturase (SCD1), i.e., an enzyme converting saturated fatty acids to Δ9-monounsaturated fatty acids, has been observed in various cancer cells. This increase in expression and activity has also been associated with cancer aggressiveness and poor patient outcome. Previous studies have also indicated the SCD1 involvement in increased cancer cells proliferation, growth, migration, epithelial to mesenchymal transition, metastasis, chemoresistance, and maintenance of cancer stem cells properties. Hence, SCD1 seems to be a player in malignancy development and may be considered a novel therapeutic target in cancers, including hepatocellular carcinoma (HCC). This review study aims to discuss the impact of SCD1 as a major component in lipid signaling in HCC.

Age Evolution of Lipid Accretion Rate in Boars Selected for Lean Meat and Duroc Barrows.

Simple SummaryFat deposition profile and fatty acid biosynthesis in adipose tissues are two relevant metabolic processes for breeding companies as the fat content of meat relates to its technological, organoleptic, and nutritional quality. Age, breed, and sex have a great impact on fat metabolism. Therefore, in the present experiment, a labeled saturated fatty acid was added to the diet of pigs belonging to three different producing types during two growth phases, to define the rate of its incorporation into body fat. In addition, the activity of the enzyme stearoyl-CoA desaturase, which promotes the conversion of some saturated fatty acids into monounsaturated, was analyzed. In the growing phase, direct incorporation of fat from diet was higher than biosynthesis in most adipose tissues, whereas in the fattening phase it was higher only in the liver, revealing the changing roles of organs in fat metabolism with age. The leaner pigs also obtained a higher fat incorporation, denoting higher reliance on dietary fatty acids for fat deposition; overall, real stearoyl-CoA desaturase activity was higher in the fattening phase.Fatty acid (FA) deposition in growing–fattening pigs is mainly based on endogenous lipid synthesis, but also direct FA incorporation from the diet. To evaluate the direct fat incorporation rates and the endogenous desaturation action of the stearoyl-CoA desaturase (SCD) enzyme, a deuterium (D)-labeled saturated FA (d35-C18:0) was added to the diet. Sixteen three-way (3W) crossbred boars, and thirty-two purebred Duroc barrows homozygous for the SCD single nucleotide polymorphism rs80912566 (16 CC/16 TT), were used. Half of the animals of each genotype belonged to the growing and fattening phases. The fractional incorporation rate (FIR) of dietary fat in growing pigs was generally higher in adipose tissues, whereas in fattening pigs it was higher in the liver. Duroc pigs exhibited lower FIRs than 3W pigs, suggesting lower rates of endogenous synthesis by 3W pigs. Real fractional unsaturation rates (FURs) increased with age by the higher FIRs in 3W pigs and the de novo synthesis pathway in Duroc genotypes. Moreover, pigs carrying the SCD_T allele showed more enhanced oleic acid biosynthesis than Duroc CC pigs. In conclusion, suitable feeding protocols should be designed for each pig type to optimize production traits, considering that the metabolic pathway of FA for its deposition may differ.

Abstract 1849: Lipid metabolites as potential diagnostic biomarkers for stearoyl-CoA desaturase 1 targeting therapy in hepatocellular carcinoma (HCC)

Abstract New effective therapies should be developed for the treatment of hepatocellular carcinoma (HCC). One of the very promising strategies is blocking the activity of stearoyl-CoA desaturase 1 (SCD1). SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis by converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). In our laboratory, we developed a novel, highly specific SCD1inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We conducted analysis of the enzymatic protein levels involved in de novo fatty acid synthesis. Protein expression levels for these enzymes don’t predict response to therapy. To determine whether lipid metabolites predict response to SSI-4 therapy, lipidomic analysis was investigated. Our studies showed thatSSI-4 sensitive cells when exposed to SSI-4 had a higher baseline level of key lipid metabolites such as phospholipids (PL), diglycerides (DAG), diglycerides (TAG), ceramides (CE), and free fatty acids (FFA),compared to insensitive cells. We are currently validating these results in our in vivo models at the tumor tissue and blood levels. Additionally, mechanistic studies are in progress to determine if SREBP1c, an AKT regulated transcription factor known to regulate each of the fatty acid synthetic enzymes plays a role in HCC fatty acid synthesis and sensitivity to SCD1 inhibition. Citation Format: Justyna Joanna Gleba. Lipid metabolites as potential diagnostic biomarkers for stearoyl-CoA desaturase 1 targeting therapy in hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1849.