stearoyl-CoA Desaturase Activity Research Articles

Polymorphisms rs55710213 and rs56334587 regulate SCD1 expression by modulating HNF4A binding

The stearoyl-CoA desaturase 1 (SCD1) gene at 10q24.31 encodes the rate limiting enzyme SCD1 that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). Dysregulated SCD1 activity has been observed in many human diseases including non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, hyperlipidemia, metabolic syndrome and several types of cancer. HNF4A is a central regulator of glucose and lipid metabolism and previous studies suggested that it is deeply involved in regulating the SCD1 activity in the liver. However, the underlying mechanisms on whether and how SCD1 is regulated by HNF4A have not been explored in detail. In this study, we found that HNF4A regulates SCD1 expression by directly binding to the key regulatory regions in the SCD1 locus. Knocking down of HNF4A significantly downregulated the expression of SCD1. Variants rs55710213 and rs56334587 in intron 5 of SCD1 directly reside in a canonical HNF4A binding site. The GG haplotype of rs55710213 and rs56334587 is associated with decreased SCD1 activity by disrupting the binding of HNF4A, which further decreased the enhancer activity and SCD1 expression. In conclusion, our study demonstrated that SCD1 is directly regulated by HNF4A, which may be helpful in the understanding of the altered metabolic pathways in many diseases associated with dysregulated SCD1 or HNF4A or both.

The molecular and metabolic program by which white adipocytes adapt to cool physiologic temperatures.

Although visceral adipocytes located within the body’s central core are maintained at approximately 37°C, adipocytes within bone marrow, subcutaneous, and dermal depots are found primarily within the peripheral shell and generally exist at cooler temperatures. Responses of brown and beige/brite adipocytes to cold stress are well studied; however, comparatively little is known about mechanisms by which white adipocytes adapt to temperatures below 37°C. Here, we report that adaptation of cultured adipocytes to 31°C, the temperature at which distal marrow adipose tissues and subcutaneous adipose tissues often reside, increases anabolic and catabolic lipid metabolism, and elevates oxygen consumption. Cool adipocytes rely less on glucose and more on pyruvate, glutamine, and, especially, fatty acids as energy sources. Exposure of cultured adipocytes and gluteal white adipose tissue (WAT) to cool temperatures activates a shared program of gene expression. Cool temperatures induce stearoyl-CoA desaturase-1 (SCD1) expression and monounsaturated lipid levels in cultured adipocytes and distal bone marrow adipose tissues (BMATs), and SCD1 activity is required for acquisition of maximal oxygen consumption at 31°C.

Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity

Abstract Immune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The role of different FA species, and their impacts on humoral immunity remains poorly understood. Here we report that proliferating B cells require monounsaturated FAs (MUFA) to maintain mitochondrial metabolism and mTOR activity, and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Immune challenges increase systemic MUFA availability in vivo. Furthermore, B cell extrinsic Stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.

Prolonged Changes in Hepatic Mitochondrial Activity and Insulin Sensitivity by High Fructose Intake in Adolescent Rats.

Persistence of damage induced by unhealthy diets during youth has been little addressed. Therefore, we investigated the impact of a short-term fructose-rich diet on liver metabolic activity in adolescent rats and the putative persistence of alterations after removing fructose from the diet. Adolescent rats were fed a fructose-rich diet for three weeks and then switched to a control diet for further three weeks. Body composition and energy balance were not affected by fructose-rich diet, while increased body lipids and lipid gain were found after the rescue period. Switching to a control diet reversed the upregulation of plasma fructose, uric acid, lipocalin, and haptoglobin, while plasma triglycerides, alanine aminotransferase, lipopolysaccharide, and tumor necrosis factor alpha remained higher. Hepatic steatosis and ceramide were increased by fructose-rich diet, but reversed by returning to a control diet, while altered hepatic response to insulin persisted. Liver fatty acid synthase and stearoyl-CoA desaturase (SCD) activities were upregulated by fructose-rich diet, and SCD activity remained higher after returning to the control diet. Fructose-induced upregulation of complex II-driven mitochondrial respiration, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, and peroxisome proliferator activated receptor α also persisted after switching to control diet. In conclusion, our results show prolonged fructose-induced dysregulation of liver metabolic activity.

DDRE-05. STEAROYL COA DESATURASE IS ESSENTIAL FOR REGULATION OF ENDOPLASMIC RETICULUM HOMEOSTASIS AND TUMOR GROWTH IN GLIOBLASTOMA CANCER STEM CELLS

INTRODUCTIONEmerging evidence suggest that, in addition to glucose, fatty acids can also drive glioma growth. Increased lipid synthesis is one of the metabolic hallmarks of cancer, and indeed, unsaturated fatty acids (UFA) are particularly abundant in glioblastoma. However, the exact role of fatty acids in GBM tumors remains unclear. Blocking fatty acids synthesis can present a new therapy for GBM.METHODSThrough targeted inhibitors screening on glioma stem cells (GSCs), we found that they are highly susceptible to Stearoyl CoA Desaturase 1 (SCD1) inhibitors. SCD1 is a key enzyme responsible for the conversion of saturated fatty acids (SFA) to UFA. 1) Through cell-based assays and immunoblot analyses, we tried to understand the role of UFA, SFA and SCD1 in GSCs differentiation and proliferation. We investigated the mechanism between fatty acids and tumor growth through ER stress modulation linked with SCD1 expression. 2) As we found that GSCs are highly susceptible to SCD1 inhibition, we tested CAY, SCD1 inhibitor, in GSCs orthotopic mouse models and assess its effect on tumor growth and overall survival.RESULTSWe found that GSCs with extensive self-renewal capacity have an increased dependence on SCD1 activity. Through immunoblot analyses, we demonstrated that SCD1 inhibition exacerbates ER stress through accumulation of SFA and SCD1-mediated UFA synthesis mitigates ER stress. Survival analyses between SCD1 inhibitor-treated group and control group showed significant survival benefit in SCD1-inhibitor-treated group, in both mesenchymal (p=0.008, 35 days vs 18) and proneural (p=0.0002) type glioma cells (n=8/groups).CONCLUSIONSWe demonstrate that SCD1, the fatty acid desaturase, is essential for the maintenance of glioblastoma cancer stem cells. SCD1 is activated by ER stress and exerts a cytoprotective function by regulating ER homeostasis, thus favoring survival and tumor growth. Pharmacological targeting of SCD1 exhibits potent therapeutic efficacy in brain tumor mouse models.

Short-Term Consumption of Pomegranate Juice Alleviates Some Metabolic Disturbances in Overweight Patients with Dyslipidemia.

Pomegranate juice (PJ) has potential positive effects in patients with metabolic disturbances due to a high content of polyphenols. The objective of this study was to evaluate effects of a 2-week consumption of dietary doses of PJ on blood pressure, lipid metabolism, and oxidative stress markers in overweight patients with dyslipidemia. Twenty-four patients, 8 males and 16 females, 40-60 years of age, with established overweight and dyslipidemia were randomly assigned into intervention group, who consumed 300 mL of PJ daily for 2 weeks, or control group. After 2 weeks of juice intake, intervention group had significantly lower diastolic blood pressure, low-density lipoprotein cholesterol, aminotransferase, and activity of glutathione peroxidase. Furthermore, patients who consumed PJ had reduced percentage of docosahexaenoic acid (22:6n-3, DHA) in plasma phospholipids and increased estimated activity of stearoyl-CoA desaturase. In erythrocytes, we found a significant increase in the levels of dihomo-γ- linolenic acid (20:3n-6, DGLA) and DHA, as well as in estimated activity of Δ6 desaturase, and a decrease in estimated activity of Δ5 desaturase. These results show that even a short-term consumption of dietary doses of PJ exerts beneficial effects and affects lipid metabolism in overweight patients with dyslipidemia.

Improved organotypic skin model with reduced quantity of monounsaturated ceramides by inhibiting stearoyl-CoA desaturase-1

Full thickness models (FTM) are 3D in vitro skin cultures that resemble the native human skin (NHS) to a great extent. However, the barrier function of these skin models is reduced. The skin barrier is located in the stratum corneum (SC) and consists of corneocytes embedded in a lipid matrix. In this matrix, deviations in the composition of the FTMs lipid matrix may contribute to the impaired skin barrier when compared to NHS. One of the most abundant changes in lipid composition is an increase in monounsaturated lipids for which stearoyl-CoA desaturase-1 (SCD-1) is responsible. To improve the SC lipid composition, we reduced SCD-1 activity during the generation of the FTMs. These FTMs were subsequently assessed on all major aspects, including epidermal homeostasis, lipid composition, lipid organization, and barrier functionality. We demonstrate that SCD-1 inhibition was successful and resulted in FTMs that better mimic the lipid composition of FTMs to NHS by a significant reduction in monounsaturated lipids. In conclusion, this study demonstrates an effective approach to normalize SC monounsaturated lipid concentration and may be a valuable tool in further optimizing the FTMs in future studies.

Участие Δ9-десатураз в регуляции обменных процессов

Lens opacity, which leads to cataract, is one of the most complicated issues in ophthalmology. Pathophysiology of cataract progression is far from being clearly established. Despite low lipid content in the lens of the eye, there is an assumption that they and their predecessors may be involved in the development of this disease. Given the many roles of monounsaturated fatty acids, it can be expected that variations in stearoyl-Coa desaturase activity will affect a number of key physiological processes.

Stearoyl-CoA Desaturase-Mediated Monounsaturated Fatty Acid Availability Supports Humoral Immunity

SUMMARYImmune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The roles of different FA species and their impacts on humoral immunity remain poorly understood. Here, we report that proliferating B cells require monounsaturated FAs (MUFAs) to maintain mitochondrial metabolism and mTOR activity and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Furthermore, B cell-extrinsic stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.

Lipid ratios representing SCD1, FADS1, and FADS2 activities as candidate biomarkers of early growth and adiposity.

BackgroundAltered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort.MethodsLipidomics was performed on the plasma of APOE*3 Leiden, Ldlr-/-.Leiden, and the wild-type C57BL/6J mice to capture candidate biomarkers predicting subsequent obesity parameters after exposure to high-fat diet. The identified candidate biomarkers were mapped onto corresponding lipid metabolism pathways and were investigated in the Cambridge Baby Growth Study. Infants’ growth and adiposity were measured at 0-24 months. Capillary dried blood spots were sampled at 3 months for lipid profiling analysis.FindingsFrom the mouse models, cholesteryl esters were correlated with subsequent weight gain and other obesity parameters after HFD period (Spearman's r≥0.5, FDR p values <0.05) among APOE*3 Leiden and Ldlr-/-.Leiden mice, but not among the wild-type C57BL/6J. Pathway analysis showed that those identified cholesteryl esters were educts or products of desaturases activities: stearoyl-CoA desaturase-1 (SCD1) and fatty acid desaturase (FADS) 1 and 2. In the human cohort, lipid ratios affected by SCD1 at 3 months was inversely associated with 3-12 months weight gain (B±SE=-0.31±0.14, p=0.027), but positively with 12-24 months weight and adiposity gains (0.17±0.07, p=0.02 and 0.17±0.07, 0.53±0.26, p=0.04, respectively). Lipid ratios affected by SCD1 and FADS2 were inversely associated with adiposity gain but positively with height gain between 3-12 months.InterpretationFrom murine models to human setting, the ratios of circulating lipid species indicating key desaturase activities in lipid metabolism were associated with subsequent body size increase, providing a potential tool to predict early life weight gain.

Monounsaturated Fatty Acids in Obesity-Related Inflammation.

Obesity is an important aspect of the metabolic syndrome and is often associated with chronic inflammation. In this context, inflammation of organs participating in energy homeostasis (such as liver, adipose tissue, muscle and pancreas) leads to the recruitment and activation of macrophages, which secrete pro-inflammatory cytokines. Interleukin-1β secretion, sustained C-reactive protein plasma levels and activation of the NLRP3 inflammasome characterize this inflammation. The Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. This enzyme catalyzes the generation of monounsaturated fatty acids (MUFAs)—major components of triglycerides stored in lipid droplets—from saturated fatty acid (SFA) substrates. In this review, we describe the molecular effects of specific classes of fatty acids (saturated and unsaturated) to better understand the impact of different diets (Western versus Mediterranean) on inflammation in a metabolic context. Given the beneficial effects of a MUFA-rich Mediterranean diet, we also present the most recent data on the role of SCD1 activity in the modulation of SFA-induced chronic inflammation.

BET Inhibition Induces Vulnerability to MCL1 Targeting Through Upregulation of Fatty Acid Synthesis Pathway in Breast Cancer

The development of effective targeted therapies for the treatment of basal-like breast cancers remains challenging. Here, we demonstrate that cellular stress engendered by BET inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancers. Consequently, co-targeting MCL1 and BET is highly synergistic in in vitro and in vivo breast cancer models. The mechanism of adaptive response to BET inhibition involves upregulation of critical lipid metabolism enzymes including the rate-limiting enzyme stearoyl-CoA desaturase (SCD). Changes in the lipid metabolism are associated with increases in cell motility and membrane fluidity as well as transitions in cell morphology. The structural changes in the cell membrane leads to re-localization and activation of HER2/EGFR which can be interdicted by inhibiting SCD activity. Active HER2/EGFR, in turn, induces accumulation of MCL1 protein and therapeutic vulnerability to MCL1 inhibitors. The BET protein, lipid metabolism and receptor tyrosine kinase activation cascade is observed in patient cohorts of basal-like and HER2-amplified breast cancers. Drug response and genomics analyses revealed that MCL1 copy number alterations, including low-level gains, are selectively enriched in basal-like breast cancers and associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) and gains (>50%) in basal-like breast cancers suggests that BET and MCL1 co-inhibition may have therapeutic utility in this aggressive subtype.

Nicotinamide Phosphoribosyltransferase Inhibitors Induce Apoptosis of AML Stem Cells through Dysregulation of Lipid Metabolism

Current chemotherapeutic regimens for acute myeloid leukemia (AML) often fail to eliminate leukemic stem cells (LSCs) which contribute to disease relapse. A key step towards the development of more effective therapies is the identification of vulnerabilities that are unique to LSCs. Here, we sought to identify LSC-specific metabolic dependencies by performing a flow cytometry-based screen of 110 metabolically-focused drugs against a primary human AML sample. This sample harbored distinct subsets defined by CD34 and CD38 expression, and LSC activity assayed by xenotransplantation was restricted to the CD34+CD38- fraction. Through this screen, we found that inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the rate-limiting step in the NAD+ salvage pathway, preferentially depleted CD34+CD38- cells, implicating NAMPT inhibitors as potential anti-LSC agents. To evaluate the therapeutic potential of NAMPT inhibitors, we focused on KPT-9274, a small-molecule NAMPT inhibitor currently under clinical development for other cancer types. Treatment with KPT-9274 depleted the CD34+CD38- fraction across multiple primary human AML samples through induction of apoptosis. The preferential sensitivity of CD34+CD38- cells to NAMPT inhibition correlated with a lower basal level of intracellular NAD+ and greater dependency on NAMPT activity for NAD+ generation relative to the other fractions. In contrast, normal CD34+ HSPCs were largely resistant to the cytotoxic effects of KPT-9274 due to their capacity to utilize the Preiss-Handler pathway for NAD+ generation. Consistent with the in vitro findings, KPT-9274 treatment significantly reduced LSC activity as determined by secondary engraftment potential in 2 of 3 patient-derived xenograft (PDX) models of human AML and had minimal impact on normal HSC activity in mice engrafted cord blood cells. To gain mechanistic insights into how NAMPT inhibition induces cell death, we performed transcriptomic analysis of sorted CD34+CD38- cells treated with KPT-9274. This analysis revealed a striking upregulation of genes involved in cholesterol and lipid synthesis including the stearoyl-CoA desaturase (SCD) gene. The upregulated genes were highly enriched for known targets of the sterol regulatory element binding protein (SREBP) transcription factors. Functional studies demonstrated that this transcriptional response was protective against the cytotoxic effect of NAMPT inhibition in AML cells. To uncover the metabolic basis of this protective effect, we performed global metabolomic profiling of AML cells treated with KPT-9274 and observed a decrease in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) upon drug treatment. This drop in MUFA:SFA ratio reflected a reduction in SCD activity which catalyzes the desaturation of SFAs to MUFAs in a NADPH-dependent reaction. Since depletion of intracellular MUFAs could trigger apoptosis, we hypothesized that the SREBP response might protect against cell death through upregulation of SCD activity and consequent increase in MUFA synthesis. In line with this hypothesis, we found that exogenous oleic acid, a MUFA, completely rescued cell death induced by KPT-9274, while treatment with SCD inhibitors sensitized AML cells to the cytotoxic effects of NAMPT inhibition. To explore the translational application of our findings, we tested whether dipyridamole (DP), a clinically approved anti-platelet agent with inhibitory activity against SREBP signaling, can be repurposed to enhance the anti-leukemic effects of KPT-9274. We showed that treatment with DP, at non-toxic concentrations, potentiated the cytotoxicity of KPT-9274 against AML cells in vitro. Importantly, in vivo combination treatment with KPT-9274 and DP effectively targeted LSC activity in a PDX model that was refractory to KPT-9274 as single agent. In summary, our findings demonstrate that LSCs are preferentially dependent on NAMPT activity for survival over non-LSCs and normal HSCs. We further uncovered that NAMPT inhibition results in dysregulation of lipid homeostasis and induces a lipogenic response coordinated by SREBPs that protects AML cells against NAD+ depletion. These findings offer insights into drug combination strategies to enhance the efficacy of NAMPT inhibitors and provide the rationale for testing NAMPT inhibitors in the treatment of AML in clinical trials. Disclosures Dick: Bristol-Myers Squibb/Celgene: Research Funding. Wang:Trilium therapeutics: Patents &amp; Royalties: There is an existing license agreement between TTI and University Health Network and J.C.Y.W. may be entitled to receive financial benefits further to this license and in accordance with UHN's intellectual property policies. .

The hepatic lipidome and HNF4α and SHBG expression in human liver.

Low plasma levels of sex hormone-binding globulin (SHBG) are a marker for obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The transcription factor HNF4α is a major determinant of hepatic SHBG expression and thereby serum SHBG levels, and mediates in part the association of low SHBG with hyperinsulinemia and hepatic steatosis. We analyzed the lipidome in human liver specimens from a cohort of patients who underwent hepatic resection as a treatment for cancer, providing insight into hepatic lipids in those without extreme obesity or the clinical diagnosis of NAFLD or non-alcoholic steatohepatitis. Both steatosis and high HOMA-IR were associated with higher levels of saturated and unsaturated FA, other than arachidonic, with the most dramatic rise in 18:1 oleate, consistent with increased stearoyl-CoA desaturase activity. Individuals with low HOMA-IR had low levels of total hepatic fatty acids, while both low and high fatty acid levels characterized the high HOMA-IR group. Both insulin resistance and high levels of hepatic fat were associated with low expression levels of HNF4α and thereby SHBG, but the expression of these genes was also low in the absence of these determinants, implying additional regulatory mechanisms that remain to be determined. The relationship of all FA studied to HNFα and SHBG mRNAs was inverse, and similar to that for total triglyceride concentrations, irrespective of chain length and saturation vs unsaturation.

Menin‑MLL inhibitors induce ferroptosis and enhance the anti‑proliferative activity of auranofin in several types of cancer cells.

Menin‑mixed‑lineage leukemia (MLL) inhibitors have potential for use as therapeutic agents for MLL‑rearranged leukemia. They are also effective against solid cancers, such as breast cancer. The present study demonstrated that menin‑MLL inhibitors, such as MI‑463, unexpectedly induced the ferroptotic cell death of several cancer cell lines. MI‑463 at a double‑digit nM concentration markedly decreased the viable number of OVCAR‑8 ovarian cancer cells for 3days. Ferrostatin‑1 (a ferroptosis inhibitor) almost completely abrogated the MI‑463‑induced decrease in viable cell numbers. Furthermore, the cancer cell‑killing activity was inhibited by N‑acetylcysteine [a scavenger of reactive oxygen species (ROS)], deferoxamine (DFO, an iron chelator), PD146176 (a specific inhibitor of arachidonate 15‑lipoxygenase), idebenone (a membrane‑permeable analog of CoQ10) and oleic acid [a monounsaturated fatty acid and one of the end products of stearoyl‑CoA desaturase 1 (SCD1)], whereas Z‑VAD‑FMK (an apoptosis inhibitor) had a negligible effect on cell death. It was also found that MI‑463 in combination with auranofin (a thioredoxin reductase inhibitor) synergistically increased cancer the death of breast, ovarian, pancreatic and lung cancer cell lines (88%, 14/16 cell lines). The synergistic induction of cell death was abrogated by ferroptosis inhibitor and DFO. Inhibitors of SCD1, similar to MI‑463, also enhanced cancer cell death synergistically with auranofin, while inhibitors of SCD1 and MI‑463 did not additively induce cell death. Treatment with zinc protoporphyrin‑9, a specific inhibitor of heme oxygenase‑1 (HO‑1), markedly attenuated the cell death induced by MI‑463 plus auranofin. On the whole, these results suggest that the MI‑463‑induced decrease in cell viability may be at least partly associated with the inhibition of SCD1 activity. In addition, the potent induction of HO‑1 contributed to the synergistic effects of MI‑463 plus auranofin. Therefore, menin‑MLL inhibitors, such as MI‑463, in combination with auranofin represent an effective therapeutic approach for several types of cancer via the induction of ferroptosis.

Stearoyl-CoA Desaturase Mediated Monounsaturated Fatty Acid Availability Supports Humoral Immunity

Immune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The role of different FA species, and their impacts on humoral immunity remains poorly understood. Here we report that proliferating B cells require monounsaturated FAs (MUFA) to maintain mitochondrial metabolism and mTOR activity, and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Furthermore, B cell extrinsic Stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.

Abstract LB-015: Yap reprograms de novo lipogenesis to fuel liver cancer

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer, originating from liver cells known as hepatocytes. At the molecular level, HCC is driven by transcription factors which are able to reprogram metabolism to support tumorigenesis that are still poorly understood. The Yes-associated protein (Yap) is the nuclear effector of the Hippo pathway, responsible in regulating organ size control and metabolism. Metabolic reprogramming has recently emerged as a fundamental hallmark of cancer. In our previous studies, we found that Yap integrates the anabolic demands of tumour growth by reprogramming glutamine and glucose metabolism to support nucleotide biosynthesis. The central aim of this study was to determine the role that Yap plays in regulating lipid metabolism in the context of liver cancer. We took advantage of a larval zebrafish model in which a hyperactivated form of Yap is specifically expressed in hepatocytes (lf:YapS87A;lf:NLS-mcherry). We found that the expression of Yap was sufficient to stimulate de novo lipogenesis (DNL) and induce lipid droplet formation in hepatocytes (steatosis). To determine whether the stimulation of DNL was required for oncogenic growth, we exposed larvae to pharmacological inhibitors of DNL and examined the impact on growth at the cellular level by multiphoton microscopy. Strikingly, we identified that fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD) inhibitors suppressed Yap-driven growth. To complement these studies, we took a genetic approach using CRISPR to generate FAS and SCD KO zebrafish larvae and we found that Yap-driven growth required both FAS and SCD. Importantly both chemical and genetic suppression of FAS and SCD activity had no effect on normal liver growth. Together, these findings suggest that oncogenic Yap-driven growth is conditionally dependent upon the stimulation of DNL. Consequently, these studies provide a rationale for examining the clinical efficacy of DNL inhibitors to combat liver cancer. Citation Format: Talhah M. Salmi, Srimayee Vaidyanathan, Malcolm J. McConville, Kristin K. Brown, Andrew G. Cox. Yap reprograms de novo lipogenesis to fuel liver cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-015.

Sciadonic acid derived from pine nuts as a food component to reduce plasma triglycerides by inhibiting the rat hepatic \u03949-desaturase

Sciadonic acid (Scia) is a Δ5-olefinic fatty acid that is particularly abundant in edible pine seeds and that exhibits an unusual polymethylene-interrupted structure. Earlier studies suggested that Scia inhibited the in vitro expression and activity of the Stearoyl-CoA Desaturase 1 (SCD1), the hepatic Δ9-desaturase involved in the formation of mono-unsaturated fatty acids. To confirm this hypothesis, rats were given 10% Scia in diets balanced out with n-6 and n-3 fatty acids. In those animals receiving the Scia supplement, monoene synthesis in the liver was reduced, which was partly attributed to the inhibition of SCD1 expression. As a consequence, the presence of Scia induced a 50% decrease in triglycerides in blood plasma due to a reduced level of VLDL-secreted triglycerides from the liver. In non-fasting conditions, results showed that Scia-induced inhibition of SCD1 led to a decrease in the proportions of 16:1n-7 and 18:1n-7 in the liver without impacting on the level of 18:1n-9, suggesting that only triglycerides with neosynthesized monoenes are marked out for release. In conclusion, this in vivo study confirms that Scia highly inhibits SCD1 expression and activity. The work was performed on normo-triglyceride rats over six weeks, suggesting promising effects on hyper-triglyceridemic models.

“Islets therapeutic checkpoint: Inhibition of stearoyl‐CoA desaturase impairs lipid droplet morphology and metabolism during palmitotoxicity of pancreatic β‐cells”

Study objectiveHyperglycemia, chronic insulin resistance in peripheral tissues and progressive insufficiency of pancreatic β‐cell function constitute main components in pathogenesis of type 2 diabetes (T2D). Obesity‐associated elevated levels of circulating fatty acids (FA) and defects in lipid metabolism regulation trigger pancreatic β‐cell failure. The precise molecular mechanism of saturated and unsaturated FA‐derived β‐cell demise remains rudimentary. Ultimately, stearoyl‐CoA desaturase 1 (SCD1), the rate limiting enzyme catalyzing the biosynthesis of monounsaturated FA is indispensable in protection of β‐cells from lipotoxicity and provide them with substrates for signaling molecules and membrane building blocks. During metabolic overload, lipid droplets (LD) are dedicated to accumulate surplus lipids in pancreatic β‐cells. Therefore, the present study aims to determine whether diminished SCD1 activity affects LD biogenesis, content and disposal, hence leading towards deregulation of β‐cell metabolism and function during lipid oversupply.MethodsThe experiments were performed in INS‐1E cells, an insulinoma β‐cell line, treated independently or in combination with palmitate (16:0) and SCD1 inhibitor. Also, murine pancreatic islets from the wild type littermates and SCD1−/− animals were analysed. The biochemical characteristics of LD was assessed by Oil Red O staining and BODIPY 493/503. The FA composition in constituent neutral lipids and phospholipids of LD was evaluated by the GC/MS.ResultsAccordingly, we demonstrate that inhibition of SCD1 activity diminished the accumulation of triacylglycerols, cholesteryl esters and phosphatidylcholine by over 45% (±0.02), 25% (±0.03) and 40% (±0.09), respectively in comparison to INS‐1E cells treated with palmitate independently. The number of LD/cell was reduced by over 30% (±0.08) within aforementioned experimental group. We observed significant changes in the diameter, compactness, and desaturation status of the LD in SCD1‐ablated and palmitic acid‐treated pancreatic β‐cells. Such an effect was linked to modified expression of adipose triglyceride lipase (ATGL), CTP:phosphocholine cytidylyltransferase (CCTα), lysophosphatidylcholine acyltransferase 2 (LPCAT), phospholipase D (PC‐PLD), acetyl‐CoA acetyltransferase 1 (ACAT1), and perilipins (PLIN). Overall lipidome of the LDs was enriched in 18:2n‐6 and 20:4n‐6 FAs. Pancreatic islets demonstrated to have more unsaturated profile of the PC class which was followed by changes in abundance of the proteins involved in phospholipid synthesis and remodeling.ConclusionsOur results point out on the novel mechanism of SCD1‐mediated regulation of metabolic LD remodeling in pancreatic β‐cells, shedding a light on the foundations of lipotoxicity‐mediated β‐cell failure.Support or Funding InformationThis work was supported by the National Science Centre grants UMO 2015/19/D/NZ4/03705 (JJ) and UMO‐2017/27/N/NZ3/01987 (AMD), and by The National Centre for Research and Development grant STRATEGMED 3/305813/2/NCBR/2017 (AD).

Effect of ursodeoxycholic acid on lipid metabolism: through the prism of evidence from 2019.

After the discovery of the method of ursodeoxycholic acid’s (UDCA) synthesis and the publication of evidence confirming its ability to reduce the lithogenic properties of bile, active clinical use of UDCA began in the world. This drug, which has pleiotropic effect (choleretic, cytoprotective, immunomodulatory, antiapoptic, litholytic, hypocholesterolemic), has proven its effectiveness in the treatment various diseases: primary biliary cholangitis, intrahepatic cholestasis of pregnancy, gallstone disease.&#x0D; Being a tertiary bile acid, UDCA stimulates bile acid synthesis by reducing the circulating fibroblast growth factor 19 and inhibiting the activation of the farnesoid X-receptor (FXR), which leads to the induction of cholesterol-7α-hydroxylase, a key enzyme in the synthesis of bile acid de novo, mediating the conversion of cholesterol into bile acids. Changes in the formation of bile acids and cholesterol while taking UDCA intake is accompanied by activation of the main enzyme of cholesterol synthesis - 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under the influence of UDCA the activity of stearoyl-Coa desaturase (SCD) in visceral white adipose tissue increases. According to studies conducted in 2019, UDCA improves lipid metabolism by regulating the activity of the ACT/mTOR signaling pathway, reduces the synthesis of cholesterol, decreases the fractional synthesis rate of cholesterol and the fractional synthesis rate of triglycerides. It has been proved that UDCA is accompanied by a decrease in the level of total cholesterol and low density lipoprotein cholesterol.