Fatty Acid Desaturation Research Articles

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

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

EjFAD8 Enhances the Low-Temperature Tolerance of Loquat by Desaturation of Sulfoquinovosyl Diacylglycerol (SQDG).

Loquat (Eriobotrya japonica Lindl.) is an evergreen fruit tree of Chinese origin, and its autumn-winter flowering and fruiting growth habit means that its fruit development is susceptible to low-temperature stress. In a previous study, the triploid loquat (B431 × GZ23) has been identified with high photosynthetic efficiency and strong resistance under low-temperature stress. Analysis of transcriptomic and lipidomic data revealed that the fatty acid desaturase gene EjFAD8 was closely associated with low temperatures. Phenotypic observations and measurements of physiological indicators in Arabidopsis showed that overexpressing-EjFAD8 transgenic plants were significantly more tolerant to low temperatures compared to the wild-type. Heterologous overexpression of EjFAD8 enhanced some lipid metabolism genes in Arabidopsis, and the unsaturation of lipids was increased, especially for SQDG (16:0/18:1; 16:0/18:3), thereby improving the cold tolerance of transgenic lines. The expression of ICE-CBF-COR genes were further analyzed so that the relationship between fatty acid desaturase and the ICE-CBF-COR pathway can be clarified. These results revealed the important role of EjFAD8 under low-temperature stress in triploid loquat, the increase expression of FAD8 in loquat under low temperatures lead to desaturation of fatty acids. On the one hand, overexpression of EjFAD8 in Arabidopsis increased the expression of ICE-CBF-COR genes in response to low temperatures. On the other hand, upregulation of EjFAD8 at low temperatures increased fatty acid desaturation of SQDG to maintain the stability of photosynthesis under low temperatures. This study not only indicates that the EjFAD8 gene plays an important role in loquat under low temperatures, but also provides a theoretical basis for future molecular breeding of loquat for cold resistance.

Abstract 1250: Aberrant polyunsaturated fatty acids desaturation impairs survival and anti-tumor immunity of tumor resident memory CD8+ T cell in hepatocellular carcinoma

Abstract Background & Aim: Aberrant polyunsaturated fatty acids (PUFAs) metabolism is closely associated with the immunosuppressive tumor microenvironment (TME). Tissue-resident memory T cell (Trm) plays a central role against solid tumors, including HCC, depending on the uptake of exogenous fatty acids to maintain survival and anti-tumor immunity. Here we aimed to explore the potential interaction in TME between HCC-derived PUFAs and Trm function in a series of integrated clinical, basic and translational studies. Methods: Tissue interstitial fluids (TIFs) were isolated and analyzed from fresh paired adjacent tissues and HCC for detecting the PUFAs alterations in the HCC TME. Integrated analyses were performed in multiple public databases and local cohorts. Fatty acid desaturase 1 (FADS1) knockdown (KD) HCC cell line was generated to observe the tumor biology and metabolic function. The effects of FADS1 knockout (KO) or overexpression were investigated in multiple spontaneous HCC mouse models via hydrodynamic tail vein injection (HTVI) in vivo. Mutation landscape analysis was used to explore the mechanism of FADS1 transcription. Therapeutic interventions by downregulating FADS1 were also evaluated in vivo. Results: Clinically, we found that the arachidonic acid (ARA) level was enriched in HCC TIFs. A rate-limiting enzyme controlling PUFA biosynthesis, especially ARA production from dihomo-γ-linolenic acid (DGLA), FADS1, was overexpressed in HCC patients. High expression of FADS1 predicted poor survival and was negatively correlated with CD8+CD103+Trm infiltration. Moreover, in the local clinical trial, we noticed that the expression of FADS1 was upregulated in non-response patients with anti-PD-1 mAb treatment. Functionally, we demonstrated that the ARA level was decreased in the conditioned medium (CM) from FADS1 KD cells. Applying CM prolonged the survival of CD8+CD103+Trm ex vivo. FADS1 KO inhibited tumor development by increasing intratumor infiltration and function of CD8+CD103+Trm. In contrast, overexpression of FADS1 promoted HCC progression by restraining immune surveillance in vivo. Mechanistically, we found that the expression of FADS1 was upregulated in the TP53 mutation group by analyzing the mutation landscape of HCC. Mutant P53 protein could bind to the promoter region of FADS1. Therapeutically, recombinant adeno-associated 8 (rAAV8)-shRNAs delivery and anti-PD-1 mAb administration inhibited the tumor growth of anti-PD-1 mAb treatment-resistant HCC model driven by CTNNB1N90 and MYC. Conclusions: We demonstrated that mutant P53 protein directly promoted FADS1 transcription, increasing ARA accumulation in HCC TME. FADS1 remodeling the metabolic patterns of PUFAs impaired CD8+CD103+Trm anti-tumor immunity, possibly leading to HCC progression. Citation Format: Tao Ding, Li Pang, Runying Long, Shinuan Zeng, Kevin TP Ng, Qingmei Zhang, Zhiwei Chen, Kwan Man. Aberrant polyunsaturated fatty acids desaturation impairs survival and anti-tumor immunity of tumor resident memory CD8+ T cell in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1250.

Integrated metabolomics and lipidomics analyses suggest the temperature-dependent lipid desaturation promotes aflatoxin biosynthesis in Aspergillus flavus.

Temperature is one of the main factors affecting aflatoxin (AF) biosynthesis in Aspergillus flavus. Previous studies showed that AF biosynthesis is elevated in A. flavus at temperatures between 28°C-30°C, while it is inhibited at temperatures above 30°C. However, little is known about the metabolic mechanism underlying temperature-regulated AF biosynthesis. In this study, we integrated metabolomic and lipidomic analyses to investigate the endogenous metabolism of A. flavus across 6 days of mycelia growth at 28°C (optimal AF production) and 37°C (no AF production). Results showed that both metabolite and lipid profiles were significantly altered at different temperatures. In particular, metabolites involved in carbohydrate and amino acid metabolism were up-regulated at 37°C on the second day but down-regulated from days three to six. Moreover, lipidomics and targeted fatty acids analyses of mycelia samples revealed a distinct pattern of lipid species and free fatty acids desaturation. High degrees of polyunsaturation of most lipid species at 28°C were positively correlated with AF production. These results provide new insights into the underlying metabolic changes in A. flavus under temperature stress.

Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.

Recent advances in targeting leukemic stem cells (LSCs) using venetoclax with azacitidine (ven + aza) has significantly improved outcomes for de novo acute myeloid leukemia (AML) patients. However, patients who relapse after traditional chemotherapy are often venetoclax-resistant and exhibit poor clinical outcomes. We previously described that fatty acid metabolism drives oxidative phosphorylation (OXPHOS) and acts as a mechanism of LSC survival in relapsed/refractory AML. Here, we report that chemotherapy-relapsed primary AML displays aberrant fatty acid and lipid metabolism, as well as increased fatty acid desaturation through the activity of fatty acid desaturases 1 and 2, and that fatty acid desaturases function as a mechanism of recycling NAD+ to drive relapsed LSC survival. When combined with ven + aza, the genetic and pharmacologic inhibition of fatty acid desaturation results in decreased primary AML viability in relapsed AML. This study includes the largest lipidomic profile of LSC-enriched primary AML patient cells to date and indicates that inhibition of fatty acid desaturation is a promising therapeutic target for relapsed AML.

Desaturation of sebaceous-type saturated fatty acids through the SCD1 and the FADS2 pathways impacts lipid neosynthesis and inflammatory response in sebocytes in culture.

Sebum is a lipid-rich mixture secreted by the sebaceous gland (SG) onto the skin surface. By penetrating through the epidermis, sebum may be involved in the regulation of epidermal and dermal cells in both healthy and diseased skin conditions. Saturated and monounsaturated fatty acids (FAs), found as free FAs (FFAs) and in bound form in neutral lipids, are essential constituents of sebum and key players of the inflammatory processes occurring in the pilosebaceous unit in acne-prone skin. Little is known on the interplay among uptake of saturated FFAs, their biotransformation, and induction of proinflammatory cytokines in sebocytes. In the human SG, palmitate (C16:0) is the precursor of sapienate (C16:1n-10) formed by insertion of a double bond (DB) at the Δ6 position catalysed by the fatty acid desaturase 2 (FADS2) enzyme. Conversely, palmitoleate (C16:1n-7) is formed by insertion of a DB at the Δ9 position catalysed by the stearoyl coenzyme A desaturase 1 (SCD1) enzyme. Other FFAs processed in the SG, also undergo these main desaturation pathways. We investigated lipogenesis and release of IL-6 and IL-8 pro-inflammatory cytokines in SZ95 sebocytes in vitro after treatment with saturated FFAs, that is, C16:0, margarate (C17:0), and stearate (C18:0) with or without specific inhibitors of SCD1 and FADS2 desaturase enzymes, and a drug with mixed inhibitory effects on FADS1 and FADS2 activities. C16:0 underwent extended desaturation through both SCD1 and FADS2 catalysed pathways and displayed the strongest lipoinflammatory effects. Inhibition of desaturation pathways proved to enhance lipoinflammation induced by SFAs in SZ95 sebocytes. Palmitate (C16:0), margarate (C17:0), and stearate (C18:0) are saturated fatty acids that induce different arrays of neutral lipids (triglycerides) and dissimilar grades of inflammation in sebocytes.

Temporal changes in muscle characteristics during growth in the goat

This study aimed to explore the temporal accumulative process of functional components and take insight into their dynamic regulatory metabolic pathways in the longissimus during growth in goats. Results showed that the intermuscular fat content, cross-sectional area and fast- to slow-switch fiber ratio of the longissimus were synchronously increased from d1 to d90. The dynamic profiles of functional components and transcriptomic pathways of the longissimus both exhibited two distinct phases during animal development. Expression of genes involved in de novo lipogenesis was increased from birth to weaning, leading to the accumulation of palmitic acid in the first phase. Accumulation of functional oleic acid, linoleic acid and linolenic acid in the second phase was dominatingly driven by enhancement in expression of genes related to fatty acid elongation and desaturation after weaning. A shift from serine to glycine production was observed after weaning, which was linked to the expression profile of genes involved in their interconversion. Our findings systematically reported the key window and pivotal targets of the functional components' accumulation process in the chevon.

Growth and fatty acid distribution over lipid classes in Nannochloropsis oceanica acclimated to different temperatures.

After light, temperature is the most relevant environmental parameter in outdoors cultivation of microalgae. Suboptimal and supraoptimal temperatures negatively impact growth and photosynthetic performance with a subsequent effect on lipid accumulation. It is generally recognised that lower temperatures trigger an increase in fatty acid desaturation while higher temperatures trigger the opposite reaction. The effect of temperature on lipid classes has been less studied in microalgae and in certain cases, the effect of light cannot be completely excluded. In this research, the effect of temperature on growth, photosynthesis, and lipid class accumulation in Nannochloropsis oceanica was studied at a fixed light gradient with a constant incident light intensity (670 μmol m-2 s-1). A turbidostat approach was used to achieve temperature acclimated cultures of Nannochloropsis oceanica. Optimal growth was found at 25-29°C, while growth was completely arrested at temperatures higher than 31°C and lower than 9°C. Acclimation to low temperatures triggered a decrease in absorption cross section and photosynthesis rates with a tipping point at 17°C. Reduced light absorption was correlated with a decrease in content of the plastid lipids monogalactosyldiacylglycerol and sulfoquinovosyldiacylglycerol. The increase of diacylglyceryltrimethylhomo-serine content at lower temperatures indicated a relevant role of this lipid class in temperature tolerance. Triacylglycerol content increased at 17°C and decreased at 9°C emphasising a metabolic switch in stress response. Total and polar eicosapentaenoic acid content remained constant at 3.5 and 2.4% w/w, despite the fluctuating lipid contents. Results show an extensive mobilisation of eicosapentaenoic acid between polar lipids classes at 9°C to ensure cell survival under critical conditions.

AdipoR2 promotes fatty acid desaturation, elongation and incorporation into phospholipids in response to membrane rigidification.

AdipoR2 and its C. elegans homolog PAQR-2 are hydrolases activated by membrane rigidification that signal via S1P to promote desaturase transcription. Separately, AdipoR2 and PAQR-2 can recruit a fatty acid elongation complex associated with ACSL4 that channels unsaturated fatty acids towards incorporation into phospholipids, hence promoting membrane fluidity. The AdipoR2/PAQR-2 proteins are therefore essential for membrane homeostasis in response to rigidifying conditions. Evidence from C. elegans, human and mouse models supporting this view will be presented.

Cis- and Trans-variations of Stearoyl-CoA Desaturase Provide New Insights into the Mechanisms of Diverged Pattern of Phenotypic Plasticity for Temperature Adaptation in Two Congeneric Oyster Species.

The evolution of phenotypic plasticity plays an essential role in adaptive responses to climate change; however, its regulatory mechanisms in marine organisms which exhibit high phenotypic plasticity still remain poorly understood. The temperature-responsive trait oleic acid content and its major gene stearoyl-CoA desaturase (Scd) expression have diverged in two allopatric congeneric oyster species, cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata. In this study, genetic and molecular methods were used to characterize fatty acid desaturation and membrane fluidity regulated by oyster Scd. Sixteen causative single-nucleotide polymorphisms (SNPs) were identified in the promoter/cis-region of the Scd between wild C. gigas and C. angulata. Further functional experiments showed that an SNP (g.-333C [C. gigas allele] >T [C. angulata allele]) may influence Scd transcription by creating/disrupting the binding motif of the positive trans-factor Y-box factor in C. gigas/C. angulata, which mediates the higher/lower constitutive expression of Scd in C. gigas/C. angulata. Additionally, the positive trans-factor sterol-regulatory element-binding proteins (Srebp) were identified to specifically bind to the promoter of Scd in both species, and were downregulated during cold stress in C. gigas compared to upregulated in C. angulata. This partly explains the relatively lower environmental sensitivity (plasticity) of Scd in C. gigas. This study serves as an experimental case to reveal that both cis- and trans-variations shape the diverged pattern of phenotypic plasticity, which provides new insights into the formation of adaptive traits and the prediction of the adaptive potential of marine organisms to future climate change.

Striking membrane defects in AdipoR-deficient cells

Membrane homeostasis defects likely underly numerous conditions. AdipoR1 and AdipoR2 sense excesses of saturated fatty acids in phospholipids and correct such imbalance by generating sphingosine 1-phospate (S1P) that promotes fatty acid desaturation via SREBP and PPARγ (1-3).

Do betaine lipids replace phosphatidylcholine as fatty acid editing hubs in microalgae?

Acyl editing refers to a deacylation and reacylation cycle on a lipid, which allows for fatty acid desaturation and modification prior to being removed and incorporated into other pools. Acyl editing is an important determinant of glycerolipid synthesis and has been well-characterized in land plants, thus this review begins with an overview of acyl editing in plants. Much less is known about acyl editing in algae, including the extent to which acyl editing impacts lipid synthesis and on which lipid substrate(s) it occurs. This review compares what is known about acyl editing on its major hub phosphatidylcholine (PC) in land plants with the evidence for acyl editing of betaine lipids such as diacylglyceryltrimethylhomoserine (DGTS), the structural analog that replaces PC in several species of microalgae. In land plants, PC is also known to be a major source of fatty acids and diacylglycerol (DAG) for synthesis of the neutral lipid triacylglycerol (TAG). We review the evidence that DGTS contributes substantially to TAG accumulation in algae as a source of fatty acids, but not as a precursor to DAG. We conclude with evidence of acyl editing on other membrane lipid substrates in plants and algae apart from PC or DGTS, and discuss future analyses to elucidate the role of DGTS and other betaine lipids in acyl editing in microalgae.

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.

Cellular Uptake, Metabolism and Sensing of Long-Chain Fatty Acids.

Fatty acids (FAs) are critical nutrients that regulate an organism's health and development in mammal. Long-chain fatty acids (LCFAs) can be divided into saturated and unsaturated fatty acids, depending on whether the carbon chain contains at least 1 double bond. The fatty acids that are required for humans and animals are obtained primarily from dietary sources, and LCFAs are absorbed from outside of cells in mammals. LCFAs enter cells through several mechanisms, including passive diffusion and protein-mediated translocation across the plasma membrane, the latter in which FA translocase (FAT/CD36), plasma membrane FA-binding protein (FABPpm), FA transport protein (FATP), and caveolin-1 are believed to have important functions. The LCFAs that are taken up by cells bind to FA-binding proteins (FABPs) and are transported to the specific organelles, where they are activated into acyl-CoA to target specific metabolic pathways. LCFA-CoAs can be esterified to phospholipids, triacylglycerol, cholesteryl ester, and other specialized lipids. Non-esterified free fatty acids are preferentially stored as triacylglycerol molecules. The main pathway by which fatty acids are catabolized is β-oxidation, which occurs in mitochondria and peroxisomes. stearoyl-CoA desaturase (SCD)-dependent and Fatty acid desaturases (FADS)-dependent fatty acid desaturation pathways coexist in cells and provide metabolic plasticity. The process of fatty acid elongation occurs by cycling through condensation, reduction, dehydration, and reduction. Extracellular LCFA can be mediated by membrane protein G protein-coupled receptor 40 (GPR40) or G protein-coupled receptor 120 (GPR120) to activate mammalian target of rapamycin complex 1 (mTORC1) signaling, and intracellular LCFA's sensor remains to be determined. The crystal structures of a phosphatidic acid phosphatase and a membrane-bound fatty acid elongase-condensing enzyme and other LCFA-related proteins provide important insights into the mechanism of utilization, increasing our understanding of the cellular uptake, metabolism and sensing of LCFAs.

Metabolomics analysis reveal the molecular responses of high CO2 concentration improve resistance to Pb stress of Oryza sativa L. seedlings

Rice seedlings were exposed to two CO2 concentrations (400 ± 20 and 800 ± 20 μmol mol−1) and three PbNO3 concentrations (0, 50 and 100 µmol L−1) for 10 days to explore the regulatory mechanisms of elevated CO2 for Pb stress resistance. Electrical conductivity, MDA content, SOD, POD, CAT activities and metabolomics changes were studied. Results showed that: Pb stress damaged cell membrane system, electrical conductivity and MDA content increased 49.34 % and 73.27 %, respectively, and some antioxidant enzymes activities increased. Sugar, polyol, amino acid metabolism and fatty acid β-oxidation were all enhanced to improve osmotic adjustments, maintain cell membrane stability, supply energy, nitrogen assimilates and antioxidant capacity; Under composite treatments, cell membrane damage was reduced, activities of protective enzymes increased compared with only Pb stress, POD activity increased the most (49.14 %) under severe Pb composite treatment. High CO2 caused the enhance of cells antioxidant capacity, TCA cycle intermediate products contents and fatty acid desaturation under mild Pb stress. Many sugars, polyols and amino acids contents were increased as osmotic regulatory substances by high CO2 under severe Pb stress; Secondary metabolites played an important role under Pb stress and composite treatments. The object of this study is to provide a possible molecular mechanism of rice response to Pb stress under high CO2 in the future.

Fatty acid metabolism in liver and muscle is strongly modulated by photoperiod in Fischer 344 rats.

Circadian and seasonal variations produce variations in physiological processes throughout the day and the year, respectively. In this sense, both the light and the moment of feeding are strong modulators of the central and peripheral clocks. However, little is known about its influence on certain metabolic parameters and on the composition of liver and muscle fatty acids (FA). In the present study, 24 Fischer 344 rats were exposed for 11weeks to different photoperiods, L6, L12 and L18, with 6, 12 and 18h of light/day, respectively. They were fed a standard diet. Serum metabolic parameters, gene expression of liver enzymes and gastrocnemius muscle involved in the synthesis, elongation, desaturation and β-oxidation of FA were analyzed. We have found that exposure to different hours of light has a clear effect on FA composition and gene expression in the liver. Mainly, the biosynthesis of unsaturated FA was altered in the L18 animals with respect to those exposed to L12, while the L6 did not show significant changes. At the muscle level, differences were observed in the concentration of mono and polyunsaturated FA. A multivariate analysis confirmed the differences between L12 and L18 in a significant way. We conclude that exposure to long days produces changes in the composition of liver and muscle FA, as well as changes in the gene expression of oxidative enzymes compared to exposure to L12, which could be a consequence of different seasonal eating patterns.

Atlantic salmon adapt to low dietary n-3 PUFA and warmer water temperatures by increasing feed intake and expression of n-3 biosynthesis-related transcripts

Climate change can have cascading impacts on biochemical reactions in aquatic ecosystems. Aquatic ectotherms can adapt to surrounding temperatures by using long-chain polyunsaturated fatty acids (LC-PUFAs) to maintain cell membrane fluidity. In a warming scenario, less LC-PUFA is needed to maintain fluidity. Our objective was to determine the impact of low dietary LC-PUFA and warm water temperature on growth, fatty acid (FA) storage, and expression of lipid metabolism-related transcripts in Atlantic salmon. Salmon (141g) were fed two diets (high or low LC-PUFA) at either 12°C or 16°C for 16weeks. Salmon weighed more and consumed more food at 16°C and when fed the low-LC-PUFA diet. Liver and muscle FA mostly depended on diet rather than temperature. DHA in muscle was higher at 16°C and in salmon fed the high-LC-PUFA diet. Levels of FA desaturation transcripts were more highly expressed at 16°C and in salmon fed the low-LC-PUFA diet, which suggests synthesis of LC-PUFA. Overall, with slow, chronic temperature increases, salmon may adapt to low dietary LC-PUFA by synthesizing more when required.

A review on the role of fatty acids in colorectal cancer progression.

Colorectal cancer (CRC) is the third leading cause of mortality in cancer patients. The role of fatty acids (FA) and their metabolism in cancer, particularly in CRC raises a growing interest. In particular, dysregulation of synthesis, desaturation, elongation, and mitochondrial oxidation of fatty acids are involved. Here we review the current evidence on the link between cancer, in particular CRC, and fatty acids metabolism, not only to provide insight on its pathogenesis, but also on the development of novel biomarkers and innovative pharmacological therapies that are based on FAs dependency of cancer cells.

SCD1 Sustains Homeostasis of Bulge Niche via Maintaining Hemidesmosomes in Basal Keratinocytes.

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

C/EBPα Confers Dependence to Fatty Acid Biosynthetic Pathways and Vulnerability to Lipid Oxidative Stress in FLT3-Mutant Leukemia

Despite therapeutic breakthroughs, drug resistance and relapse remain the major barrier for the treatment of patients with acute myeloid leukemia (AML). Therefore, understanding and targeting therapy-resistant AML cells responsible for relapse ("persisters") represent an urgent need in the development of new treatments. In this context, we demonstrated that the hyperactivation of mitochondrial oxidative metabolism plays a crucial role in drug resistance of AML. This high oxidative phosphorylation (OxPHOS) phenotype associated with enhanced mitochondrial BCL2 dependency and ROS detoxification is the consequence of a mitochondrial adaptation driven by inflammatory stress responses in a cAMP-PKA-ATF4-dependent manner. Targeting elevated oxidative phosphorylation (OxPHOS) activity with direct and indirect mitochondrial inhibitors sensitizes resistant cells to chemotherapy cytarabine (AraC) in AML. Furthermore, we have recently shown that the mitochondrial OxPHOS state supports IDH mutant cell proliferation and chemoresistance in a C/EBPa-dependent manner. Importantly, multi-omics analyses uncovered a coordinated activation of CEBPA and Fms-like tyrosine kinase 3 (FLT3) to control lipid metabolism in FLT3-mutant AML cells from primary AML patient specimens, cell lines, and PDX models. Mechanistically, C/EBPα regulated FASN-SCD axis to promote uptake, biosynthesis and desaturation of fatty acids (FA). We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation in leukemic cells. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress and accumulation of poly-unsaturated FA increased lipid peroxidation and vulnerability to redox stress. Accordingly, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells ex vivo and in vivo. Altogether, this study reveals a non-canonical C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application. Altogether, our works highlight the role of metabolic adaptations to support the plasticity and drug resistance in AML.