Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infltration

This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and FAO datasets were used to identify these key genes.Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain(ACADM)between KIRC and non cancer samples.The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features.The diagnostic performance of ACADM for KIRC was asessed using a diagnostic receiver operating ch aracteristic(ROC)curve.The co-expressed genes of ACADM were identifed in LinkedOmics database,and their function and pathway enrichment were analyzed.The correlation between ACADM expression level and immune infitration was analyzed by Gene Set Variation Analysis(GSVA)method Additionally,the proliferation,migration,and invasion abilities of KIRC cells were assessed after overexpressing ACADM.Following differential analysis and intersection,we identifed six hub genes,induding ACADM.We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic efect(AUC=0.916).Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis.According to correlation analysis,a variety of dinical features were associated with the expression level of ACADML By analyzing the infiltration level of immune cells,we found that ACADM may be related to the enrichment of immune cells.Finally,ACADM overexpression inhibited proliferation,migration,and invasion of KIRC cells.In conclusion,our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis.These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC,offering a reference for dinicians in diagnosis and treatment.

Transplacental induction of fatty acid oxidation in term fetal pigs by the peroxisome proliferator-activated receptor alpha agonist clofibrate

Background： To induce peroxisomal proliferator-activated receptor α（PPARα） expression and increase milk fat utilization in pigs at birth, the effect of maternal feeding of the PPARα agonist, clofibrate（2-（4-chlorophenoxy）-2-methyl-propanoic acid, ethyl ester）, on fatty acid oxidation was examined at ful-term delivery（0 h） and 24 h after delivery in this study.Each group of pigs（n = 10） was delivered from pregnant sows fed a commercial diet with or without 0.8% clofibrate for the last 7 d of gestation. Blood samples were col ected from the utero-ovarian artery of the sows and the umbilical cords of the pigs as they were removed from the sows by C-section on day 113 of gestation.Results： HPLC analysis identified that clofibric acid was present in the plasma of the clofibrate-fed sow（~4.2 μg/m L）and its offspring（~1.5 μg/m L）. Furthermore, the maternal-fed clofibrate had no impact on the liver weight of the pigs at 0 h and 24 h, but hepatic fatty acid oxidation examined in fresh homogenates showed that clofibrate increased（P 〈 0.01）^14C-accumulation in CO2 and acid soluble products 2.9-fold from [1-^14C]-oleic acid and 1.6-fold from[1-^14C]-lignoceric acid respectively. Correspondingly, clofibrate increased fetal hepatic carnitine palmitoyltransferase（CPT）and acyl-Co A oxidase（ACO） activities by 36% and 42% over controls（P 〈 0.036）. The m RNA abundance of CPT I was 20-fold higher in pigs exposed to clofibrate（P 〈 0.0001） but no differences were detected for ACO and PPARα m RNA between the two groups.Conclusion： These data demonstrate that dietary clofibrate is absorbed by the sow, crosses the placental membrane, and enters fetal circulation to induce hepatic fatty acid oxidation by increasing the CPT and ACO activities of the newborn.

Glycolytic and fatty acid oxidation genes affect the treatment and prognosis of liver cancer

BACKGROUND Metabolic reprogramming is a feature of tumour cells and is essential to support their rapid proliferation.The glycolytic activity of liver cancer cells is significantly higher than that of normal liver cells,and the rapidly proliferating tumour cells are powered by aerobic glycolysis.Lipid metabolism reprogramming enables tumour cells to meet their needs for highly proliferative growth and is an important driving force for the development of hepatocellular carcinoma(HCC).AIM To explore the influence of different metabolic subtypes of HCC and analyse their significance in guiding prognosis and treatment based on the molecular mechanism of glycolysis and fatty acid oxidation(FAO).METHODS By downloading related data from public databases including the Cancer Genome Atlas(TCGA),the Molecular Signatures Database,and International Cancer Genome Consortium,we utilised unsupervised consensus clustering to divide TCGA Liver Hepatocellular Carcinoma samples into four metabolic subgroups and compared single nucleotide polymorphism,copy number variation,tumour microenvironment,and Genomics of Drug Sensitivity in Cancer and Tumour Immune Dysfunction and Exclusion between different metabolites.The differences and causes of survival and the clinical characteristics between them were analysed,and a prognostic model was established based on glycolysis and FAO genes.Combined with the clinical features,a Norman diagram was created to compare the pros and cons of each model.RESULTS In the four metabolic subgroups,with the increase in glycolytic expression,the median survival of patients showed the worst results,while FAO showed the best.When comparing the follow-up analysis of each group,we considered that the differences between them might be related to reactive oxygen species,somatic copy number variation of key genes,and immune microenvironment.It was also found that the FAO group and the low-risk group had better efficacy and response to immune checkpoint blockade treatment and anti-tumour drugs.CONCLUSION There are obvious differences in genes,chromosomes,and clinical characteristics between metabolic subgroups.The establishment of a prognostic model could predict patient prognosis and guide clinical treatment.

Effects of medium chain triglycerides on hepatic fatty acid oxidation in clofibrate-fed newborn piglets

To investigate whether increasing tricarboxylic acid(TCA)cycle activity and ketogenic capacity would augment fatty acid(FA)oxidation induced by the peroxisome proliferator-activated receptor-alpha(PPARα)agonist clofibrate,suckling newborn piglets(n=54)were assigned to 8 groups following a 2(±clofibrate)×4(glycerol succinate[SUC],triglycerides of 2-methylpentanoic acid[T2M],valeric acid[TC5]and hexanoic acid[TC6])factorial design.Each group was fed an isocaloric milk formula containing either 0%or 0.35%clofibrate(wt/wt,dry matter basis)with 5%SUC,T2M,TC5 or TC6 for 5 d.Another 6 pigs served as newborn controls.Fatty acid oxidation was examined in fresh homogenates of liver collected on d 6 using[1-^(14)C]palmitic acid(1 mM)as a substrate(0.265μCi/μmol).Measurements were performed in the absence or presence of L-carnitine(1 mM)or inhibitors of 3-hydroxy-3-methylglutaryl-CoA synthase(L659699,1.6μM)or acetoacetate-CoA deacylase(iodoacetamide,50μM).Without clofibrate stimulation,^(14)C accumulation in CO_(2) was higher from piglets fed diets containing T2M and TC5 than SUC,but similar to those fed TC6.Under clofibrate stimulation,accumulation also was higher in homogenates from piglets fed TC5 than all other dietary treatments.Interactions between clofibrate and carnitine or the inhibitors were observed(P=0.0004)for acid soluble products(ASP).In vitro addition of carnitine increased^(14)C-ASP(P<0.0001)above all other treatments,regardless of clofibrate treatment.The percentage of^(14)C in CO_(2) was higher(P=0.0023)in TC5 than in the control group.From these results we suggest that dietary supplementation of anaplerotic and ketogenic FA could impact FA oxidation and modify the metabolism of acetyl-CoA(product ofβ-oxidation)via alteration of TCA cycle activity,but the modification has no significant impact on the hepatic FA oxidative capacity induced by PPARα.In addition,the availability of carnitine is a critical element to maintain FA oxidation during the neonatal period.

Betaine affects muscle lipid metabolism via regulating the fatty acid uptake and oxidation in finishing pig

Background： Betaine affects fat metabolism in animals, but the specific mechanism is still not clear. The purpose of this study was to investigate possible mechanisms of betaine in altering lipid metabolism in muscle tissue in finishing pigs.Methods： A total of 120 crossbred gilts（Landrace × Yorkshire × Duroc） with an average initial body weight of 70.1 kg were randomly allotted to three dietary treatments. The treatments included a corn–soybean meal basal diet supplemented with 0, 1250 or 2500 mg/kg betaine. The feeding experiment lasted 42 d.Results： Betaine addition to the diet significantly increased the concentration of free fatty acids（FFA） in muscle（P 〈 0.05）. Furthermore, the levels of serum cholesterol and high-density lipoprotein cholesterol were decreased（P 〈 0.05） and total cholesterol content was increased in muscle（P 〈 0.05） of betaine fed pigs. Experiments on genes involved in fatty acid transport showed that betaine increased expression of lipoprotein lipase（LPL）, fatty acid translocase/cluster of differentiation（FAT/CD36）, fatty acid binding protein（FABP3） and fatty acid transport protein（FATP1）（P 〈 0.05）. The abundance of fatty acid transport protein and fatty acid binding protein were also increased by betaine（P 〈 0.05）. As for the key factors involved in fatty acid oxidation, although betaine supplementation didn＇t affect the level of carnitine and malonyl-CoA, betaine increased mR NA and protein abundance of carnitine palmitransferase-1（CPT1）and phosphorylated-AMPK（P 〈 0.05）.Conclusions： The results suggested that betaine may promoted muscle fatty acid uptake via up-regulating the genes related to fatty acid transporter including FAT/CD36, FATP1 and FABP3. On the other hand, betaine activated AMPK and up-regulated genes related to fatty acid oxidation including PPARα and CPT1. The underlying mechanism regulating fatty acid metabolism in pigs supplemented with betaine is associated with the up-regulation of genes involved in fatty acid transport and fatty acid oxidation.

Inhibition of nitric oxide synthase lowers fatty acid oxidation in ~reeclampsia-like mice at early gestational stage

Background Preeclampsia is one of hypertensive disorders in pregnancy. It is associated with abnormal lipid metabolism, including fatty acid oxidation metabolism. Long chain 3-hydroxyacyI-CoA dehydrogenase （LCHAD） plays an indispensable role in the oxidation of fatty acids. It has been reported that nitric oxide （NO） is one of the regulatory factors of the fatty acid oxidation pathway. The aim of this research was to investigate whether the nitric oxide synthase （NOS）inhibitor L-NAME may cause down-regulation of LCHAD in the pathogenesis of preeclampsia.Methods Pregnant wild-type （WT） mice were treated with L-NAME or normal saline （NS） during gestation days 7-18 （early group）, days 11-18 （mid group） and days 16-18 （late group）, and apoE-/- mice served as a control. Systolic blood pressure （SBP）, urine protein, feto-placental outcome, plasma lipid levels and NO concentrations were measured, and the expression of mRNA and protein for LCHAD in placental tissue were determined by real-time polymerase chain reaction （RT-PCR） and Western blotting, respectively.Results In WT and apoE-/- mice, SBP and urinary protein increased following L-NAME injection. Fetal and placental weights and NO concentrations were reduced and total cholesterol, triglycerides and free fatty acid levels were increased in early and mid L-NAME groups in WT and apoE-/- mice, compared with the NS group. There was no significant difference between the late L-NAME group and NS group. RT-PCR and Western blotting analysis showed that the mRNA and protein levels of LCHAD expression were significantly down-regulated in the early and mid L-NAME groups but not in the late L-NAME group in the WT and apoE-/- mice compared with the corresponding NS groups.Conclusions Inhibition of NO in early and mid gestation in mice may cause hyperlipidemia and suppression of fatty acid oxidation, whereas preeclampsia-like conditions in late gestation may be a maternal vascular response to inhibition of NO.

Rhodiola crenulata extract decreases fatty acid oxidation and autophagy to ameliorate pulmonary arterial hypertension by targeting inhibiton of acylcarnitine in rats

Pulmonary arterial hypertension(PAH)is a devastating pulmonary circulation disease lacking high-efficiency therapeutics.The present study aims to decipher the therapeutic mechanism of Rhodiola crenulata,a well-known traditional chinese medicine with cardiopulmonary protection capacity,on PAH by exploiting functional lipidomics.The rat model with PAH was successfully established for first,following Rhodiola crenulata water extract(RCE)treatment,then analysis of chemical constituents of RCE was performed,additional morphologic,hemodynamic,echocardiographic measurements were examined,further targeted lipidomics assay was performed to identify differential lipidomes,at last accordingly mechanism assay was done by combining qRT-PCR,Western blot and ELISA.Differential lipidomes were identified and characterized to differentiate the rats with PAH from healthy controls,mostly assigned to acylcarnitines,phosphatidylcholines,sphingomyelin associated with the PAH development.Excitingly,RCE administration reversed high level of decadienyl-L-carnitine by the modulation of metabolic enzyme CPT1A in mRNA and protein level in serum and lung in the rats with PAH.Furthermore,RCE was observed to reduce autophagy,confirmed by significantly inhibited PPARγ,LC3B,ATG7 and upregulated p62,and inactivated LKB1-AMPK signal pathway.Notably,we accurately identified the constituents in RCE,and delineated the therapeutic mechansim that RCE ameliorated PAH through inhibition of fatty acid oxidation and autophagy.Altogether,RCE might be a potential therapeutic medicine with multi-targets characteristics to prevent the progression of PAH.This novel findings pave a critical foundation for the use of RCE in the treatment of PAH.

Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells

Tamoxifen(TAM)is the first-line endocrine therapy for estrogen receptor-positive(ER+)breast cancer(BC).However,acquired resistance occurs in∼50%cases.Meanwhile,although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients,complex signaling feedback loops exist,which can counter the effectiveness of inhibitors of this pathway.Here,we analyzed signaling pathways and metabolism in ER+MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting,quantitative polymerase chain reaction,and the Agilent Seahorse XF Analyzer.We found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant cells.Furthermore,ERRα/PGC-1βand their target genes MCAD and CPT-1 were increased and regulated by AMPK,which coincided with increased fatty acid oxidation(FAO)and autophagy in TAM-resistant cells.Inhibition of AKT feedback-activates AMPK and ERRα/PGC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT inhibitors.Therefore,our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells.Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

Effect of dietary soybean oil and antioxidants on fatty acids and volatile compounds of tail subcutaneous and perirenal fat tissues in fattening lambs

Background： Fat is the primary source of the volatiles that determine the characteristic flavors of animal products.Because unsaturated fatty acids（UFAs） contribute to changes in flavor as a result of the oxidation process, a feeding trial was performed to investigate the effects of dietary soybean oil or antioxidants on the fatty acid and volatile profiles of the tail subcutaneous（SF） and perirenal fat tissues（PF） of fattening lambs. Thirty-six Huzhou lambs were assigned to four dietary treatments in a randomized block design. The lambs＇ diets were supplemented with soybean oil（0 or 3 % of DM） or antioxidants（0 or 0.025 % of DM）.Results： Neither soybean oil nor antioxidant supplementation had an effect on lamb growth（P 〉 0.05）. In regard to tail SF, soybean oil supplementation increased the 18：2n6t（P 〈 0.05） and the total amount of volatile acids,whereas antioxidant supplementation increased the content of C18：2n6c and C18：3n3（P 〈 0.05） but had no effect on the volatiles profile. In regard to PF, dietary soybean oil supplementation increased the C18：0 content（P 〈 0.01）;decreased the C18：1（P = 0.01）, C22：1 n9（P 〈 0.01） and total UFA（P = 0.03） contents; and tended to decrease the E-2-octenal（P = 0.08）, E, E-2, 4-decadienal（P = 0.10）, 2-undecenal（P = 0.14） and ethyl 9-decenoate（P = 0.10） contents.Antioxidant supplementation did not affect either the fatty acid content or the volatiles profile in the PF.Conclusions： Tail SF and PF responded to dietary soybean oil and antioxidant supplementation in different ways. For SF, both soybean oil and antioxidant supplementation increased the levels of unsaturated fatty acids but triggered only a slight change in volatiles. For PF, soybean oil supplementation decreased the levels of unsaturated fatty acids and oxidative volatiles, but supplementation with antioxidants had little effect on PF fatty acids and the volatiles profile.

Metabolic reprogramming of the inflammatory response in the nervous system:the crossover between inflammation and metabolism

Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.

Indole alkaloids of Alstonia scholaris(L.)R.Br.alleviated nonalcoholic fatty liver disease in mice fed with high-fat diet

Alstonia scholaris(L.)R.Br(Apocynaceae)is a well-documented medicinal plant for treating respiratory diseases,liver diseases and diabetes traditionally.The current study aimed to investigate the effects of TA on non-alcoholic fatty liver disease(NAFLD).A NAFLD model was established using mice fed a high-fat diet(HFD)and administered with TA(7.5,15 and 30 mg/kg)orally for 6 weeks.The biochemical parameters,expressions of lipid metabolism-related genes or proteins were analyzed.Furthermore,histopathological examinations were evaluated with Hematoxylin-Eosin and MASSON staining.TA treatment significantly decreased the bodyweight of HFD mice.The concentrations of low-density lipoprotein(LDL),triglyceride(TG),aspartate aminotransferase(AST)and alanine aminotransferase(ALT)were also decreased significantly in TA-treated mice group,accompanied by an increase in high-density lipoprotein(HDL).Furthermore,TA alleviated hepatic steatosis injury and lipid droplet accumulation of liver tissues.The liver mRNA levels involved in hepatic lipid synthesis such as sterol regulatory element-binding protein 1C(SREBP-1C),regulators of liver X receptorα(LXRα),peroxisome proliferator activated receptor(PPAR)γ,acetyl-CoA carboxylase(ACC1)and stearyl coenzyme A dehydrogenase-1(SCD1),were markedly decreased,while the expressions involved in the regulation of fatty acid oxidation,PPARα,carnitine palmitoyl transterase 1(CPT1A),and acyl coenzyme A oxidase 1(ACOX1)were increased in TA-treated mice.TA might attenuate NAFLD by regulating hepatic lipogenesis and fatty acid oxidation.

Characteristics of glucose and lipid metabolism and the interaction between gut microbiota and colonic mucosal immunity in pigs during cold exposure

Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold and non-cold adaptation regarding glucose and lipid metabolism,gut microbiota and colonic mucosal immunological features in pigs are unknown.This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation.Moreover,the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs.Results Cold and non-cold-adapted models were established by Min and Yorkshire pigs.Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models(Yorkshire pigs),decreasing plasma glucose concentrations.In this case,cold exposure enhanced the ATGL and CPT-1αexpression to promote liver lipolysis and fatty acid oxidation.Meanwhile,the two probiotics(Collinsella and Bifidobacterium)depletion and the enrichment of two pathogens(Sutterella and Escherichia-Shigella)in colonic microbiota are not conducive to colonic mucosal immunity.However,glucagon-mediated hepatic glycogenolysis in cold-adapted pig models(Min pigs)maintained the stability of glucose homeostasis during cold exposure.It contributed to the gut microbiota(including the enrichment of the Rikenellaceae RC9 gut group,[Eubacterium]coprostanoligenes group and WCHB1-41)that favored cold-adapted metabolism.Conclusions The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa.During non-cold adaptation,cold-induced glucose overconsumption promotes thermogenesis through lipolysis,but interferes with the gut microbiome and colonic mucosal immunity.Furthermore,glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.

Retinoic acid signaling in fatty liver disease

Retinoic acid(RA)is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism.Through genomic and nongenomic actions,RA regulates a variety of physiological functions.Dysregulation of RA signaling is associated with many diseases.Targeting RA signaling has been proven valuable to human health.All-trans-RA(AtRA)and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia(APL).Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease(NAFLD).In this review article,we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD.AtRA inhibits the development and progression of NAFLD by regulating lipid metabolism,inflammation,thermogenesis,etc.

CPT1A in cancer: Tumorigenic roles and therapeutic implications

Metabolic reprogramming frequently occurs in the majority of cancers,wherein fatty acid oxidation(FAO)is usually induced and serves as a compensatory mechanism to improve energy consumption.Carnitine palmitoyltransferase 1A(CPT1A)is the rate-limiting enzyme for FAO and is widely involved in tumor growth,metastasis,and chemo-/radio-resistance.This review summarizes the most recent advances in understanding the oncogenic roles and mechanisms of CPT1A in tumorigenesis,including in proliferation and tumor growth,invasion and metastasis,and the tumor microenvironment.Importantly,CPT1A has been shown to be a biomarker for diagnosis and prognosis prediction and proved to be a candidate therapeutic target,especially for the treatment of drug-and radiation-resistant tumors.In summary,CPT1A plays remarkable roles in promoting cancer progression and is a potential anticancer therapeutic target.

Increased mitochondrial fission drives the reprogramming of fatty acid metabolism in hepatocellular carcinoma cells through suppression of Sirtuin 1

Background:Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes.Recently,abnormally increased mitochondrial fission has been observed in several types of can-cer.However,the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear.This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepa-tocellular carcinoma(HCC)cells.Methods:Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content.The rate of fatty acid oxidation was evaluated by[PH]-labelled oleic acid.The mito-chondrial morphology in HCC cells was evaluated by fluorescent staining.The expression of protein was determined by real-time PCR,imnmunohistochemistry and Western blotting.Results:Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase(FASN),acetyl-CoA carboxylasel(ACCI),and elonga-tion of very long chain fatty acid protein 6(ELOVL6),while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A(CPTIA)and acyl-CoA oxidase 1(ACOX1).Consistently,suppressed mitochondrial fission exhibited the opposite effects.Moreover,in vitro and in vivo studies revealed that mitochondrial fission-induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells.Mechanistically,mito-chondrial fission increased the acetylation level of sterol regulatory element-binding protein 1(SREBPI)and peroxisome proliferator-activated receptor coaC-tivator 1 alpha(PGC-1a)by suppressing nicotinamide adenine dinucleotide(NAD+)/Sirtuin 1(SIRTI)signaling.The elevated SREBP1 then upregulated the expression of FASN,ACC1 and ELOVL6 in HCC cells,while PGC-1c/PPARa sup-pressed the expression of CPTIA and ACOXL Conclusions:Increased mitochondrial fission plays a crucial role in the repro-gramming of lipid metabolism in HCC cells,which provides strong evidence for the use of this process as a drug target in the treatment of this malignancy.

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.

Effects of Insulin Treatment on Intracellular Lipid Metabolism in Liver of Diabetic Rats

The effects and the mechanism of insulin treatment on intracellular lipid metabolism in liver of diabetic rats were evaluated. Type 2 diabetic rats were induced by injecting the streptozotocin （25 mg/kg） and fat rich food. According to the results of oral glucose tolerance test （OGTT） and glucose-induced insulin secretion test （IRT）, the rats were divided into two groups： untreated group （UT） and insulin-treated group （IT）. Normal rats （NC） served as controls. The treatment with either Humulin N （4-6 U/kg every day）, or saline lasted for 4 weeks. Body weight, OGTT, IRT, blood lipids, intracellular lipids in liver, hepatic fatty acid oxidation and the activity of fatty acid synthase （FAS） were detected. The change of liver histology was observed. The insulin sensitivity index （ISI） was applied to assess the status of insulin resistance. The results showed that as compared with NC group, the plasma and hepatic intracellular Triglyceride （TG）, total cholesterol （TC） and free fatty acids （FFAs） were increased significantly in UT group （P〈0.05）, and lipid droplets could be seen dispersedly in the liver specimens, the hepatic fatty acid oxidation was increased markedly （P〈0.05）, while the fatty acid synthase activity decreased （P〈0.05）. Insulin treatment resulted in a further accumulation of lipids in liver by 55.7 %, 19.87 % and 22.2 % increase in TG, TC, FFAs respectively. The size of hepatocytes was enlarged and the cells were filled with fat drops. Plasma lipids showed little decrease and still significantly higher than those in NC group after the insulin treatment. Meanwhile, insulin treatment was companied by 20 % decrease in the rate of fatty acid oxidation and 31 % increase in hepatic FAS activity compared to, UT group. It was concluded that treatment with insulin on type 2 diabetic rat increases hepatic intracellular lipid accumulation by inhibiting hepatic fatty acid oxidation and activating FAS.

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Background:Abnormal expression of protein tyrosine phosphatases(PTPs)has been reported to be a crucial cause of cancer.As a member of PTPs,protein tyrosine phosphatase receptor type O(PTPRO)has been revealed to play tumor suppressive roles in several cancers,while its roles in colorectal cancer(CRC)remains to be elucidated.Hence,we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression.Methods:The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo.Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acidβ-oxidation.Results:PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer,and such a downregulation was associated with poor prognosis of patients with CRC.PTPRO silencing significantly promoted cell growth and liver metastasis.Compared with PTPRO wild-type mice,PTPROknockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium.Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways.Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis.Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase(AKT)/mammalian target of rapamycin(mTOR)signaling axis,thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element-binding protein 1(SREBP1)and its target lipogenic enzyme acetyl-CoA carboxylase alpha(ACC1)by activating the AKT/mTOR signaling pathway.Furthermore,PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator-activated receptor alpha(PPARα)and its downstream enzyme peroxisomal acyl-coenzyme A oxidase 1(ACOX1)via activating the p38/extracellular signal-regulated kinase(ERK)mitogen-activated protein kinase(MAPK)signaling pathway.Conclusions:PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

Molecular mechanism of carvedilol on attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy

Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.

The Action of p-Synephrine on Lipid Metabolism in the Perfused Rat Liver

p-synephrine and p-octopamine were found to increase lipolysis in adipocytes. The present study approaches the question if these compounds, natural products of the bitter orange (Citrus aurantium fruit), increase lipolysis and fatty acid oxidation in the liver. Experiments were done in the perfused rat liver. Non-recirculating hemoglobin-free perfusion was done using the Krebs/ Henseleit-bicarbonate buffer (pH 7.4) as perfusion fluid. Both p-synephrine and p-octopamine, at the concentrations of 100 μM, were found to stimulate the hepatic triacylglycerol lipase by 40% and 51%, respectively. These seem to be the maximal stimulations possible in the liver. In the perfused liver, p-synephrine, when present at an initial concentration of 500 μM, was able to increase the non-esterified fatty acid release after one hour of recirculating perfusion. The effects of p-synephrine on the oxidation of exogenously supplied [1-14C]octanoate and [1-14C]oleate were minimal. Only oxygen uptake, already stimulated by octanoate or oleate, was additionally increased by the infusion of p-synephrine. These results contrast with those obtained in a previous study with p-octopamine, which increased the production of 14CO2 from both [1-14C]octanoate and [1-14C]oleate. Apparently only the oxidation of endogenous fatty acids is stimulated by p-synephrine. On the other hand, both p-synephrine and p-octopamine stimulate the hepatic triacylglycerol lipase to a much lesser extent than the adipocyte lipase. It can be concluded that p-synephrine affects much more carbohydrate metabolism in the liver than lipid metabolism.