Evaluation of fatty acid metabolism and innate immunity interactions between commercial broiler, F1 layer × broiler cross and commercial layer strains selected for different growth potentials

Background： The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid（FA） metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as wel as genes involved with FA metabolism, immunity and cel ular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil：lymphocyte ratios, relative organ weights and bodyweight data were also compared.Results： Broiler bodyweight（n = 12） was four times that of layers（n = 12） by d 14 and had significantly higher carcass fat percentage compared to the cross（n = 6; P = 0.002） and layers（P = 0.017） which were not significantly different from each other（P = 0.523）. The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite al being raised on the same diet. Genes associated with FA synthesis andβ-oxidation were upregulated in the broilers compared to the layers indicating a net overal increase in FA metabolism,which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as wel as organel e stress indicators ERN1 and XBP1 were found to be nonsignificant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additional y there was no difference in heterophil： lymphocytes between any of the birds.Conclusions： The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cel ular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.

Interaction between peroxisomes and mitochondria in fatty acid metabolism

Peroxisomes and mitochondria are ubiquitously found organelles. They both are dynamic structures able to divide, to fuse and to undergo autophagic processes. Their activities are dependent on proteins that are, for most (mitochondria) or all (peroxisome) of them, synthesized in the cytosol from the nuclear genome. Nevertheless, the membrane structures and the DNA content differ between these two organelles. Mitochondria possess a small circular genome while peroxisomes don’t. The control of their dynamic is dependent on specific factors even if some of those are able to affect both. These two organelles are metabolically connected: they are both involved in lipid metabolism. They are both able to beta oxidize fatty acids and are implicated in ROS production. However, their precise function in these metabolic pathways and their physiological functions are different. While mitochondrial metabolism is closely related to energy production, peroxisome does not seem to be associated with energy production but with the production of bioactive molecules and in detoxification processes.

Identification and validation of novel prognostic fatty acid metabolic gene signatures in colon adenocarcinoma through systematic approaches

Colorectal cancer(CRC)belongs to the class of significantly malignant tumors found in humans.Recently,dysregulated fatty acid metabolism(FAM)has been a topic of attention due to its modulation in cancer,specifically CRC.However,the regulatory FAM pathways in CRC require comprehensive elucidation.Methods:The clinical and gene expression data of 175 fatty acid metabolic genes(FAMGs)linked with colon adenocarcinoma(COAD)and normal cornerstone genes were gathered through The Cancer Genome Atlas(TCGA)-COAD corroborating with the Molecular Signature Database v7.2(MSigDB).Initially,crucial prognostic genes were selected by uni-and multi-variate Cox proportional regression analyses;then,depending upon these identified signature genes and clinical variables,a nomogram was generated.Lastly,to assess tumor immune characteristics,concomitant evaluation of tumor immune evasion/risk scoring were elucidated.Results:A 8-gene signature,including ACBD4,ACOX1,CD36,CPT2,ELOVL3,ELOVL6,ENO3,and SUCLG2,was generated,and depending upon this,CRC patients were categorized within high-risk(H-R)and low-risk(L-R)cohorts.Furthermore,risk and age-based nomograms indicated moderate discrimination and good calibration.The data confirmed that the 8-gene model efficiently predicted CRC patients’prognosis.Moreover,according to the conjoint analysis of tumor immune evasion and the risk scorings,the H-R cohort had an immunosuppressive tumor microenvironment,which caused a substandard prognosis.Conclusion:This investigation established a FAMGs-based prognostic model with substantially high predictive value,providing the possibility for improved individualized treatment for CRC individuals.

Acyl-CoA synthase ACSL4:an essential target in ferroptosis and fatty acid metabolism

Long-chain acyl-coenzyme A(CoA)synthase 4(ACSL4)is an enzyme that esterifies CoA into specific polyunsaturated fatty acids,such as arachidonic acid and adrenic acid.Based on accumulated evidence,the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation.Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids;ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis,respectively.In addition,ACSL4 is an essential regulator of fatty acid(FA)metabolism.ACSL4 remodels the phospholipid composition of cell membranes,regulates steroidogenesis,and balances eicosanoid biosynthesis.In addition,ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology.Because it facilitates the cross-talk between ferroptosis and FA metabolism,ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries.In this review,we focus on the structure,biological function,and unique role of ASCL4 in various human diseases.Finally,we propose that ACSL4 might be a potential therapeutic target.

Polyphenols and pectin enriched golden kiwifruit (Actinidia chinensis) alleviates high fructose-induced glucolipid disorders and hepatic oxidative damage in rats:in association with improvement of fatty acids metabolism

This study aimed to investigate the protective effects of fleshes from two Actinidia chinensis(ACF), pericarps from two A. chinensis(ACP), and fleshes with pericarps from two A. chinensis(ACFP)on high fructose(HF)-instigated dyslipidemia, hepatic steatosis, oxidative stress, insulin resistance, and fatty acid metabolism disorders in rats. In general, the above abnormalities were improved after 10 weeks intervention of ACF, ACP, and ACFP. Especially, ACFP considerably ameliorated HF-induced abnormal changes in body weight gain, serum TC, TG, LDL-C and HDL-C levels, as well as serum and hepatic SFAs, MUFAs and PUFAs contents. ACFP also alleviated HF-induced hyperglycemia and hyperinsulinemia, stabilized HF-caused increase in hepatic MDA and serum ALT, AST levels, and restored HF-declined hepatic T-SOD and GSH-Px activities. Besides, histopathology of the liver further endorsed the protective effects of ACFP on hepatocellular injury. Moreover, ACFP increased HF-dropped acetic, propionic and butyric acid levels. Overall, ACFP employs more efficacious protective effects against HF-induced metabolic disorders and liver damage than ACF and ACP. This study delivers a scientific foundation for developing kiwifruit(counting peel)-based dietary supplements for those with glucolipid-metabolic disorders and liver damage.

When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance

The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.

The expanded role of fatty acid metabolism in cancer:new aspects and targets

Cancer cells undergo metabolic reprogramming to support cell proliferation,growth,and dissemination.Alterations in lipid metabolism,and specifically the uptake and synthesis of fatty acids(FAs),comprise onewelldocumented aspect of this reprogramming.Recent studies have revealed an expanded range of roles played by FA in promoting the aggressiveness of cancer while simultaneously identifying new potential targets for cancer therapy.This article provides a brief review of these advances in our understanding of FA metabolism in cancer,highlighting both recent discoveries and the inherent challenges caused by the metabolic plasticity of cancer cells in targeting lipid metabolism for cancer therapy.

Vitamin B1 THIAMIN REQUIRING1 synthase mediates the maintenance of chloroplast function by regulating sugar and fatty acid metabolism in rice

Vitamin B(VB1),including thiamin,thiamin monophosphate(TMP),and thiamin pyrophosphate(TPP),is an essential micronutrient for all living organisms.Nevertheless,the precise function of VB1 in rice remains unclear.Here,we described a VB1 auxotrophic mutant,chlorotic lethal seedling(cles)from the mutation of OsTH1,which displayed collapsed chloroplast membrane system and decreased pigment content.OsTH1 encoded a phosphomethylpyrimidine kinase/thiamin-phosphate pyrophosphorylase,and was expressed in various tissues,especially in seedlings,leaves,and young panicles.The VB1 content in cles was markedly reduced,despite an increase in the expression of VB1 synthesis genes.The decreased TPP content affected the tricarboxylic acid cycle,pentose phosphate pathway,and de novo fatty acid synthesis,leading to a reduction in fatty acids(C16:0 and C18:0)and sugars(sucrose and glucose)of cles.Additionally,irregular expression of chloroplast membrane synthesis genes led to membrane collapse.We also found that alternative splicing and translation allowed OsTH1 to be localized to both chloroplast and cytosol.Our study revealed that OsTH1 was an essential enzyme in VB1 biosynthesis and played crucial roles in seedling growth and development by participating in fatty acid and sugar metabolism,providing new perspectives on VB1 function in rice.

Endothelial cell metabolism in sepsis

BACKGROUND:Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure.Endothelial cells(ECs)exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.METHODS:Web of Science and PubMed were searched from inception to October 1,2022.The search was limited to the English language only.Two reviewers independently identified studies related to EC metabolism in sepsis.The exclusion criteria were duplicate articles according to multiple search criteria.RESULTS:Sixty articles were included,and most of them were cell and animal studies.These studies reported the role of glycolysis,oxidative phosphorylation,fatty acid metabolism,and amino acid metabolism in EC homeostasis.including glycolysis,oxidative phosphorylation,fatty acid metabolism and amino acid metabolism.However,dysregulation of EC metabolism can contribute to sepsis progression.CONCLUSION:There are few clinical studies on EC metabolism in sepsis.Related research mainly focuses on basic research,but some scientific problems have also been clarified.Therefore,this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis.

MiR-140 downregulates fatty acid synthesis by targeting transforming growth factor alpha(TGFA)in bovine mammary epithelial cells

Fat is an indispensable nutrient and basic metabolite for sustaining life,and milk is particularly rich in fatty acids,including a variety of saturated and unsaturated fatty acids.MicroRNA(miRNA)and mRNA play an important role in the regulation of milk fat metabolism in mammary gland tissue.It has been shown that lipid metabolism has a complex transcriptional regulation,but the mechanism by which milk fat synthesis is regulated through miRNA–mRNA interactions is poorly understood.In this study,we performed transcriptome sequencing with bovine mammary gland tissue in the late lactation(270 and 315 days after parturition)to identify the key gene that regulating milk fat metabolism.A total of 1207 differentially coexpressed genes were selected,828 upregulated genes and 379 downregulated genes were identified.The transforming growth factor alpha(TGFA)gene was selected as the target gene,and luciferase reporter assay,Western blotting and q RT-PCR were used for further study.The results demonstrated that miR-140 was an upstream regulator of TGFA,and miR-140 could inhibit(P<0.01)unsaturated fatty acid and triglyceride(TAGs)production in bovine mammary epithelial cells(BMECs).In contrast,TGFA promoted(P<0.01)unsaturated fatty acid and TAG production.Rescue experiments further indicated the mi R-140/TGFA regulatory mechanism.Taken together,these results suggest that the mi R-140/TGFA pathway can inhibit(P<0.01)milk fat metabolism and improve milk quality by genetic means.

Effects of docosahexaenoic acid or arachidonic acid supplementation on the behavior of cardiomyocytes derived from human pluripotent stem cells

Background:Human heart changes its energetic substrates from lactate and glucose to fatty acids during the neonatal period.Noticing the lack of fatty acids in media for the culture of cardiomyocytes derived from human pluripotent stem cells(hiPS-CM),researchers have supplemented mixtures of fatty acids to hiPS-CM and reported the enhancement in the maturation of hiPS-CM.In our previous studies,we separately supplemented two polyunsaturated fatty acids(PUFAs),docosahexaenoic acid(DHA)or arachidonic acid(AA),to rat fetal cardiomyocytes and found that the supplementations upregulated the expressions of mRNAs for cardiomyocyte differentiation,fatty acid metabolism,and cellular adhesion.The enhancement in cellular contractility was attributed to the improvement in intercellular connection rather than a direct enhancement of the contractile force.Methods:This study reports the successive results of the effects of DHA or AA supplementation on hiPS-CM.In addition to the contractile force and mRNA measurements used in the previous study,we further investigated the effect of different cellular aggregations on the contractile force output by means of finite element analysis,measured glucose and fatty acids metabolites,and assessed cTNT and MLC2v expressions through immunofluorecsence evaluation.Results:It showed that the sole supplementation of albumin-conjugated DHA or AA can be taken up by hiPS-CM without other uptake-enhancing factors,and the supplementations may activate the CD36_ERRγmetabolic pathway.DHA or AA supplementation increased the cellular contractile ratio on collagen gels and AA supplementation stimulated hiPS-CM aggregation to form cellular clusters.The enhancement effect on the hiPS-CM contractile force was modest since the increase in contractile force was not significant.AA supplementation was more effective than DHA supplementation because it significantly upregulated mRNA expressions of P300 and CD36.However,finite element analysis showed that the formation of clusters on a collagen gel attenuated the contractile force exerted by the gel on its surroundings.Conclusion:DHA and AA,as having been supplemented in infant formulas,have no direct and significant enhancement effect on the performance of the hiPS-CM when they were supplemented individually,although they were able to enter the cellular metabolic system.The AA supplementation showed some auxiliary effect on the maturation of hiPS-CM,which is worthy of further investigation under the consideration of membrane composition alteration and remodeling of membrane molecules.

Role of inflammatory lipid and fatty acid metabolic abnormalities induced by plastic additives exposure in childhood asthma

Lipid metabolism play an essential role in occurrence and development of asthma,and it can be disturbed by phthalate esters(PAEs)and organophosphate fame retardants(OPFRs).As a chronic infammatory respiratory disease,the occurrence risk of childhood asthma is increased by PAEs and OPFRs exposure,but it remains not entirely clear how PAEs and OPFRs contribute the onset and progress of the disease.We have profiled the serum levels of PAEs and OPFRs congeners by liquid chromatography coupled with mass spectrometry,and its relationships with the dysregulation of lipid metabolism in asthmatic,bronchitic(acute infammation)and healthy(non-infammation)children.Eight PAEs and nine OPFRs congeners were found in the serum of children(1–5 years old)from Shenzhen,and their total median levels were 615.16 ng/m L and 17.06 ng/m L,respectively.Moreover,the serum levels of mono-methyl phthalate(MMP),tri-propyl phosphate(TPP)and tri-n-butyl phosphate(TNBP)were significant higher in asthmatic children than in healthy and bronchitic children as control.Thirty-one characteristic lipids and fatty acids of asthma were screened by machine-learning random forest model based on serum lipidome data,and the alterations of infammatory characteristic lipids and fatty acids including palmitic acids,12,13-Di HODE,14,21-Di HDHA,prostaglandin D2 and Lyso PA(18:2)showed significant correlated with high serum levels of MMP,TPP and TNBP.These results imply PAEs and OPFRs promote the occurrence of childhood asthma via disrupting infammatory lipid and fatty acid metabolism,and provide a novel sight for better understanding the effects of plastic additives on childhood asthma.

Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments

BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease(NAFLD)is mainly attributed to insufficient research on its pathogenesis.The pathogenesis of TM6SF2-efficient NAFLD remains unclear,resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.AIM To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.METHODS Liver samples collected from both NAFLD mouse models and human participants(80 cases)were used to evaluate the expression of TM6SF2 by using western blotting,immunohistochemistry,and quantitative polymerase chain reaction.RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2.Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD.MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.RESULTS Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models.TM6SF2 overexpression can reduce hepatic lipid accumulation,suggesting a protective role for TM6SF2 in a high-fat diet(HFD).Downregulation of TM6SF2,simulating the TM6SF2 E167K mutation condition,increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis,accompanied by impaired fatty acid oxidation.Owing to the potential effect of TM6SF2 deficiency on lipid metabolism,the application of an acetyl-CoA carboxylase inhibitor(MK-4074)could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.CONCLUSION TM6SF2 plays a protective role in the HFD condition;its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism,and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.

Research progress on intervention of traditional Chinese medicine on myocardial glucose and lipid metabolism in heart failure

Disorder of energy metabolism is a major pathological change in the progression of heart failure.This process leads to insufficient myocardial energy and further aggravates cardiac dysfunction.Disorders of metabolic substrate utilization,mainly glucose and fatty acids,play an important role in this process.Research over the years has shown that some traditional Chinese medicines or compound prescriptions whose main role is to replenish qi and warm yang have good effects in regulating energy metabolism disorders.It has been found that some active ingredients in traditional Chinese medicine can regulate the uptake and utilization of myocardial cell metabolic substrate,so that the metabolism of myocardial cells can be adjusted in a direction that is beneficial to the body under hypoxic conditions,increasing the overall energy supply of the myocardium and improving heart function.This article reviewed the research of traditional Chinese medicine intervention on glucose and lipid metabolism of heart failure myocardial cells,and preliminarily summarizes the law and mechanism of traditional Chinese medicine intervention in heart failure myocardial glucose and fatty acid metabolism,hoping to provide clues for energy metabolism therapy research from the perspective of traditional Chinese medicine.

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.

Growth performance,fatty acid composition,and lipid metabolism are altered in groupers(Epinephelus coioides)by dietary fish oil replacement with palm oil

In this study,we conducted a 56-d feeding trial to investigate the effects of replacing the fish oil(FO)with palm oil(PO)on the performance,tissue fatty acid(FA)composition,and mRNA levels of genes related to hepatic lipid metabolism in grouper(Epinephelus coioides).Five isolipidic(13%crude lipid)and isonitrogenous(48%CP)diets were formulated by incrementally adding PO to the control diet(25%fish meal and 9%added FO)to replace FO in the control diets.Triplicate groups of 30 groupers(initial weight:12.6±0.1 g)were fed one of the diets twice daily,to apparent satiety.The replacement of FO with 50%PO revealed maximum growth without affecting the performance and whole-body proximate compositions,and replacing FO with 100%PO revealed a comparable(P>0.05)growth with that of the control diet,suggesting PO as a suitable alternative to FO.The analysis of FA profiles in the dorsal muscle and liver though reflected the FA profile of the diet,PO substitutions above 50%could compromise(P<0.05)the FA profile in the liver and flesh of the fish species in comparison with the control diet.Furthermore,the mRNA levels of FAS,G6PD,LPL,PPARА,and D6FAD genes in the liver had positive linear and/or quadratic responses,but the SCD,HSL,ATGL,FABP,SREBP-1C and ELOVL5 had the opposite trend,with increasing dietary PO inclusion levels,whereas the mRNA level of ACC was not affected by dietary treatments.The optimal level of PO substitution for FO was estimated to be 47.1%of the feed,based on the regression analysis of percent weight gains against dietary PO inclusion levels;however,it might affect the FA profile in the liver and flesh of the fish species,and further study is required to investigate whether the changes in tissue FA composition will affect the welfare and market value over a production cycle of grouper.

Transcriptome and Metabolome Analyses of Sea Cucumbers Apostichopus japonicus in Southern China During the Summer Aestivation Period

Aestivation is a common strategy of sea cucumbers(Apostichopus japonicus)in response to high-temperature conditions.Previous studies have individually investigated the immune and physiological alterations at the aestivation stage.However,these studies have not evaluated the relationship between immunity and physiology.In this study,we explored the transcriptome and metabolome of A.japonicus during the aestivation stage to study the relationship.The transcriptome analysis of dormant(aestivation)and revived A.japonicus generated 2368 differentially expressed genes,including 927 downregulated genes and 1441 upregulated genes.Based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses,the downregulated genes in the dormant group were found to be involved in DNA replication,RNA metabolic process,and protein metabolism,which results in the inhibition of motility,skeletal development,neural activity,cell proliferation,and development of A.japonicus.In contrast,the upregulated genes were found to be associated with fatty acid metabolism,carbohydrate hydrolysis,and phagocytosis.In the metabolome analysis,the downregulated metabolites were found to be associated with fatty acid metabolism,starch and sucrose metabolism,and TCA cycle.This indicates that dormant sea cucumbers consume reserved carbohydrates and fatty acids to maintain low levels of energy supply.The protein-protein interaction network analysis further revealed that carbohydrate hydrolysis promoted phagocytosis activity in the dormant group.This study provides new insights into potential molecular mechanisms of sea cucumber survival in high-temperature conditions,which is critical in aquaculture of sea cucumbers.

Targeting PPARαin low ambient temperature exposure-induced cardiac dysfunction and remodeling

The present study demonstrates that the down-regulation of peroxisome proliferator-activated receptor-α(PPARα)results in chronic low ambient temperature(LT)exposure-induced cardiac dysfunction and remodeling,emphasizing the therapeutic potential of PPARαactivation strategies(e.g.,fenofibrate treatment)in LT-associated cardiac injury.

Nanoparticle-Mediated Lipid Metabolic Reprogramming of T Cells in Tumor Microenvironments for Immunometabolic Therapy

We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.

Lipid metabolism in tumor-infiltrating T cells: mechanisms and applications

As an essential part of adaptive immunity,T cells coordinate the immune responses against pathogens and cancer cells.Lipid metabolism has emerged as a key regulator for the activation,differentiation,and effector functions of T cells.Therefore,uncovering the molecular mechanisms by which lipid metabolism dictates T cell biology is of vital importance.The tumor microenvironment is a hostile milieu,i.e.often characterized by nutrient restriction.In this environment,various cells,such as T cells and cancer cells,reprogram their metabolism,including their lipid metabolism,to meet their energy and functional needs.Here,we review the participation of fatty acid and cholesterol metabolism homeostasis in orchestrating T cell biology.We demonstrate how the tumor microenvironment reshapes the lipid metabolism in T cells.Importantly,we highlight the current cancer therapeutic interventions that target fatty acid and cholesterol metabolism of T cells.By offering a holistic understanding of how lipid metabolic adaption by T cells facilitates their immunosurveillance in the tumor microenvironment,we believe this review and the future studies might inspire the next-generation immunotherapies.