The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitu...The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitus.However,the underlying mechanisms remain incompletely understood.Metabolism plays an essential role in the biological system.Monitoring of metabolic changes in response to disease conditions or drug treatment is critical for better understanding of the pathophysiological mechanisms.In this study,metabolic profiling analysis by gas chromatography-mass spectrometry integrated with targeted analysis by liquid chro matography-mass spectrometry was carried out in plasma samples of db/db diabetic mice after six-week treatment of PPARδagonist GW501516.GW501516 treatment significantly altered levels of metabolites,such as branched-chain amino acids(BCAAs),BCAA metabolites(3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid),long-chain fatty acids,uric acid and ketone bodies(3-hydroxybutyric acid and 2-hydroxybutyric acid)which are all associated with the impaired systemic insulin sensitivity.The pre sent results indicate the beneficial effect of PPARδagonist in alleviating insulin resistance of diabetic mice by favorably modulating metabolic profile,thus providing valuable information in understanding the therapeutic potential of PPARδagonists in correcting metabolic dysfunction in diabetes.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is well-known for inefficient early diagnosis,with most patients diagnosed at advanced stages.Increasing evidence indicates that elevated plasma levels of branched-chain amino aci...Pancreatic ductal adenocarcinoma(PDAC)is well-known for inefficient early diagnosis,with most patients diagnosed at advanced stages.Increasing evidence indicates that elevated plasma levels of branched-chain amino acids(BCAAs)are associated with an increased risk of pancreatic cancer.Branched-chain amino acid transaminase 2(BCAT2)is an important enzyme in BCAA catabolism that reversibly catalyzes the initial step of BCAA degradation to branched-chain acyl-CoA.Here,we show that BCAT2 is acetylated at lysine 44(K44),an evolutionarily conserved residue.BCAT2 acetylation leads to its degradation through the ubiquitin–proteasome pathway and is stimulated in response to BCAA deprivation.cAMP-responsive element-binding(CREB)-binding protein(CBP)and SIRT4 are the acetyltransferase and deacetylase for BCAT2,respectively.CBP and SIRT4 bind to BCAT2 and control the K44 acetylation level in response to BCAA availability.More importantly,the K44R mutant promotes BCAA catabolism,cell proliferation,and pancreatic tumor growth.Collectively,the data from our study reveal a previously unknown regulatory mechanism of BCAT2 in PDAC and provide a potential therapeutic target for PDAC treatment.展开更多
基金supported by Hong Kong Research Grants Council(No.C4024-16W)National Natural Science Foundation of China(No.91939302)Health and Medical Research Fund,Hong Kong Government(No.05161746)。
文摘The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitus.However,the underlying mechanisms remain incompletely understood.Metabolism plays an essential role in the biological system.Monitoring of metabolic changes in response to disease conditions or drug treatment is critical for better understanding of the pathophysiological mechanisms.In this study,metabolic profiling analysis by gas chromatography-mass spectrometry integrated with targeted analysis by liquid chro matography-mass spectrometry was carried out in plasma samples of db/db diabetic mice after six-week treatment of PPARδagonist GW501516.GW501516 treatment significantly altered levels of metabolites,such as branched-chain amino acids(BCAAs),BCAA metabolites(3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid),long-chain fatty acids,uric acid and ketone bodies(3-hydroxybutyric acid and 2-hydroxybutyric acid)which are all associated with the impaired systemic insulin sensitivity.The pre sent results indicate the beneficial effect of PPARδagonist in alleviating insulin resistance of diabetic mice by favorably modulating metabolic profile,thus providing valuable information in understanding the therapeutic potential of PPARδagonists in correcting metabolic dysfunction in diabetes.
基金supported by the Ministry of Science and Technology(2019YFA0801703)the National Natural Science Foundation of China(No.81790250,81790253,91959202 and 81802745)the Innovation Program of Shanghai Municipal Education Commission(N173606).
文摘Pancreatic ductal adenocarcinoma(PDAC)is well-known for inefficient early diagnosis,with most patients diagnosed at advanced stages.Increasing evidence indicates that elevated plasma levels of branched-chain amino acids(BCAAs)are associated with an increased risk of pancreatic cancer.Branched-chain amino acid transaminase 2(BCAT2)is an important enzyme in BCAA catabolism that reversibly catalyzes the initial step of BCAA degradation to branched-chain acyl-CoA.Here,we show that BCAT2 is acetylated at lysine 44(K44),an evolutionarily conserved residue.BCAT2 acetylation leads to its degradation through the ubiquitin–proteasome pathway and is stimulated in response to BCAA deprivation.cAMP-responsive element-binding(CREB)-binding protein(CBP)and SIRT4 are the acetyltransferase and deacetylase for BCAT2,respectively.CBP and SIRT4 bind to BCAT2 and control the K44 acetylation level in response to BCAA availability.More importantly,the K44R mutant promotes BCAA catabolism,cell proliferation,and pancreatic tumor growth.Collectively,the data from our study reveal a previously unknown regulatory mechanism of BCAT2 in PDAC and provide a potential therapeutic target for PDAC treatment.
