Long-chain acyl-Co A synthetase(ACSL) family members include five different ACSL isoforms, each encoded by a separate gene and have multiple spliced variants. ACSLs on endoplasmic reticulum and mitochondrial outer mem...Long-chain acyl-Co A synthetase(ACSL) family members include five different ACSL isoforms, each encoded by a separate gene and have multiple spliced variants. ACSLs on endoplasmic reticulum and mitochondrial outer membrance catalyze fatty acids with chain lengths from 12 to 20 carbon atoms to form acyl-Co As, which are lipid metabolic intermediates and involved in fatty acid metabolism, membrane modifications and various physiological processes. Gain- or lossof-function studies have shown that the expression of individual ACSL isoforms can alter the distribution and amount of intracellular fatty acids. Changes in the types and amounts of fatty acids, in turn, can alter the expression of intracellular ACSLs. ACSL family members affect not only the proliferation of normal cells, but the proliferation of malignant tumor cells. They also regulate cell apoptosis through different signaling pathways and molecular mechanisms. ACSL members have individual functions in fatty acid metabolism in different types of cells depending on substrate preferences, subcellular location and tissue specificity, thus contributing to liver diseases and metabolic diseases, such as fatty liver disease, obesity, atherosclerosis and diabetes. They are also linked to neurological disorders and other diseases. However, the mechanisms are unclear. This review addresses new findings in the classification and properties of ACSLs and the fatty acid metabolismassociated effects of ACSLs in diseases.展开更多
Long-chain acyl coenzyme A synthetase(ACSL) is a member of the synthetase family encoded by a multigene family;it plays an important role in the absorption and transport of fatty acid.Here we review the roles of ACSL ...Long-chain acyl coenzyme A synthetase(ACSL) is a member of the synthetase family encoded by a multigene family;it plays an important role in the absorption and transport of fatty acid.Here we review the roles of ACSL in the regulating absorption and transport of fatty acid,as well as the connection between ACSL and some metabolic diseases.展开更多
Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family c...Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological functions.Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and liver.In this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty acids.Additionally,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed.Moreover,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.展开更多
AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin C.METHODS:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expre...AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin C.METHODS:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expressed as 6xHis-tagged enzymes.Ni 2+-affinity purified recombinant enzymes were assayed at pH 7.5 or pH 9.5 in the presence or absence of triacsin C.In addition,ACSL5 transfected CaCo2 cells and intestinal human mucosa were monitored.ACSL5 expression in cellular systems was verified using Western blot and immunofluorescence.The ACSL assay mix included TrisHCl(pH 7.4),ATP,CoA,EDTA,DTT,MgCl 2,[9,103 H] palmitic acid,and triton X-100.The 200 μL reaction was initiated with the addition of solubilized,purified recombinant proteins or cellular lysates.Reactions were terminated after 10,30 or 60 min of incubation with Doles medium.RESULTS:Expression of soluble recombinant ACSL proteins was found after incubation with isopropyl betaD-1-thiogalactopyranoside and after ultracentrifugation these were further purified to near homogeneity with Ni 2+-affinity chromatography.Triacsin C selectively and strongly inhibited recombinant human ACSL5 protein at pH 7.5 and pH 9.5,as well as recombinant rat ACSL1(sensitive control),but not recombinant rat ACSL5(insensitive control).The IC50 for human ACSL5 was about 10 μmol/L.The inhibitory triacsin C effect was similar for different incubation times(10,30 and 60 min) and was not modified by the N-or C-terminal location of the 6xHis-tag.In order to evaluate ACSL5 sensitivity to triacsin C in a cellular environment,stable human ACSL5 CaCo2 transfectants and mechanically dissected normal human intestinal mucosa with high physiological expression of ACSL5 were analyzed.In both models,ACSL5 peak activity was found at pH 7.5 and pH 9.5,corresponding to the properties of recombinant human ACSL5 protein.In the presence of triacsin C(25 μmol/L),total ACSL activity was dramatically diminished in human ACSL5 transfectants as well as in ACSL5-rich human intestinal mucosa.CONCLUSION:The data strongly indicate that human ACSL5 is sensitive to triacsin C and does not compensate for other triacsin C-sensitive ACSL isoforms.展开更多
基金Supported by National Natural Science Foundation of China,No.81373465
文摘Long-chain acyl-Co A synthetase(ACSL) family members include five different ACSL isoforms, each encoded by a separate gene and have multiple spliced variants. ACSLs on endoplasmic reticulum and mitochondrial outer membrance catalyze fatty acids with chain lengths from 12 to 20 carbon atoms to form acyl-Co As, which are lipid metabolic intermediates and involved in fatty acid metabolism, membrane modifications and various physiological processes. Gain- or lossof-function studies have shown that the expression of individual ACSL isoforms can alter the distribution and amount of intracellular fatty acids. Changes in the types and amounts of fatty acids, in turn, can alter the expression of intracellular ACSLs. ACSL family members affect not only the proliferation of normal cells, but the proliferation of malignant tumor cells. They also regulate cell apoptosis through different signaling pathways and molecular mechanisms. ACSL members have individual functions in fatty acid metabolism in different types of cells depending on substrate preferences, subcellular location and tissue specificity, thus contributing to liver diseases and metabolic diseases, such as fatty liver disease, obesity, atherosclerosis and diabetes. They are also linked to neurological disorders and other diseases. However, the mechanisms are unclear. This review addresses new findings in the classification and properties of ACSLs and the fatty acid metabolismassociated effects of ACSLs in diseases.
基金Supported by the National Natural Science Foundation of China(81373465)
文摘Long-chain acyl coenzyme A synthetase(ACSL) is a member of the synthetase family encoded by a multigene family;it plays an important role in the absorption and transport of fatty acid.Here we review the roles of ACSL in the regulating absorption and transport of fatty acid,as well as the connection between ACSL and some metabolic diseases.
基金Supported by the Interdisziplinäres Zentrum für Klinische Forschung(IZKF-MSP-06)of University Hospital Jena.
文摘Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological functions.Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and liver.In this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty acids.Additionally,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed.Moreover,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.
基金Supported by Deutsche Forschungsgemeinschaft, No. GA785/6-1Deutsche Krebshilfe, No. 109313the Rotationsprogramm of the Medical Faculty RWTH Aachen University (to Kaemmerer E)
文摘AIM:To investigate whether human acyl-CoA synthetase 5(ACSL5) is sensitive to the ACSL inhibitor triacsin C.METHODS:The ACSL isoforms ACSL1 and ACSL5 from rat as well as human ACSL5 were cloned and recombinantly expressed as 6xHis-tagged enzymes.Ni 2+-affinity purified recombinant enzymes were assayed at pH 7.5 or pH 9.5 in the presence or absence of triacsin C.In addition,ACSL5 transfected CaCo2 cells and intestinal human mucosa were monitored.ACSL5 expression in cellular systems was verified using Western blot and immunofluorescence.The ACSL assay mix included TrisHCl(pH 7.4),ATP,CoA,EDTA,DTT,MgCl 2,[9,103 H] palmitic acid,and triton X-100.The 200 μL reaction was initiated with the addition of solubilized,purified recombinant proteins or cellular lysates.Reactions were terminated after 10,30 or 60 min of incubation with Doles medium.RESULTS:Expression of soluble recombinant ACSL proteins was found after incubation with isopropyl betaD-1-thiogalactopyranoside and after ultracentrifugation these were further purified to near homogeneity with Ni 2+-affinity chromatography.Triacsin C selectively and strongly inhibited recombinant human ACSL5 protein at pH 7.5 and pH 9.5,as well as recombinant rat ACSL1(sensitive control),but not recombinant rat ACSL5(insensitive control).The IC50 for human ACSL5 was about 10 μmol/L.The inhibitory triacsin C effect was similar for different incubation times(10,30 and 60 min) and was not modified by the N-or C-terminal location of the 6xHis-tag.In order to evaluate ACSL5 sensitivity to triacsin C in a cellular environment,stable human ACSL5 CaCo2 transfectants and mechanically dissected normal human intestinal mucosa with high physiological expression of ACSL5 were analyzed.In both models,ACSL5 peak activity was found at pH 7.5 and pH 9.5,corresponding to the properties of recombinant human ACSL5 protein.In the presence of triacsin C(25 μmol/L),total ACSL activity was dramatically diminished in human ACSL5 transfectants as well as in ACSL5-rich human intestinal mucosa.CONCLUSION:The data strongly indicate that human ACSL5 is sensitive to triacsin C and does not compensate for other triacsin C-sensitive ACSL isoforms.
