To study the effect of the toxic secondary bile acid lithocholic acid （LCA） on the expression of fibroblast growth factor 19 （FGF19） in intestinal cells and to characterize the pregnane-X-receptor （PXR） response...To study the effect of the toxic secondary bile acid lithocholic acid （LCA） on the expression of fibroblast growth factor 19 （FGF19） in intestinal cells and to characterize the pregnane-X-receptor （PXR） response of the FGF19 promoter region. METHODS： The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy- cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors, RESULTS： LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two poten- tial binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor （RXR） and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activ- ity in intestinal cells. CONCLUSION： LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.展开更多
The dietary intervention of calorie restriction(CR)is known to have the most profound effects on healthspan and lifespan across several species.In two recent back-to-back articles published in Nature,Qu et al.[1,2]rev...The dietary intervention of calorie restriction(CR)is known to have the most profound effects on healthspan and lifespan across several species.In two recent back-to-back articles published in Nature,Qu et al.[1,2]revealed that lithocholic acid(LCA),a singular secondary bile acid found to be elevated in the serum of calorie-restricted mice,is sufficient to mimic the effects of CR by delaying the onset of age-associated phenotypes in mice,and promoting lifespan extension in nematodes and flies.The authors showed that the anti-ageing effects of LCA are mediated through a conserved mechanism resulting in the activation of the lysosomal adenosine-monophosphate(AMP)-activated protein kinase(AMPK)pathway through the TUB-like protein 3(TULP3)-sirtuin(SIRT)-vacuolar H+-ATPase(v-ATPase)axis tomediate thebenefits of CR.展开更多
Bacterial infections have become a global issue that requires urgent attention,particularly regarding to emergence of multidrug resistant bacteria.We developed quaternary amine-containing antimicrobial poly(bile acid)...Bacterial infections have become a global issue that requires urgent attention,particularly regarding to emergence of multidrug resistant bacteria.We developed quaternary amine-containing antimicrobial poly(bile acid)s that contain a hydrophobic core of lithocholic acid in the main-chain.Interestingly,by choosing appropriate monomers,these cationic polymers can form core-shell micelles.These polymers exhibited biocidal activity against both Gram-positive and Gram-negative bacterial species.It is demonstrated that the micelles can deliver hydrophobic antibiotics that functionally have dual antimicrobial activities.Cytotoxicity assays against HeLa cells showed dosage-dependent toxicity for polymers with longer linkers.展开更多
The disequilibrium between the production of reactive oxygen(ROS) and nitrogen(RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-produ...The disequilibrium between the production of reactive oxygen(ROS) and nitrogen(RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-products of electron transport chain. Most of the time the intestine responds adequately against the oxidative stress, but with aging or under conditions that exacerbate the ROS and/or RNS production, the defenses are not enough and contribute to developing intestinal pathologies. The endogenous antioxidant defense system in gut includes glutathione(GSH) and GSH-dependent enzymes as major components. When the ROS and/or RNS production is exacerbated, oxidative stress occurs and the intestinal Ca2+ absorption is inhibited. GSH depleting drugs such as DLbuthionine-S,R-sulfoximine, menadione and sodium deoxycholate inhibit the Ca2+ transport from lumen to blood by alteration in the protein expression and/or activity of molecules involved in the Ca2+ transcellular and paracellular pathways through mechanisms of oxidative stress, apoptosis and/or autophagy. Quercetin, melatonin, lithocholic and ursodeoxycholic acids block the effect of those drugs in experimental animals by their antioxidant, anti-apoptotic and/or anti-autophagic properties. Therefore, they may become drugs of choice for treatment of deteriorated intestinal Ca2+ absorption under oxidant conditions such as aging, diabetes, gut inflammation and other intestinal disorders.展开更多
The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocy...The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocytes)in bile formation.The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases,such as primary biliary cholangitis or primary sclerosing cholangitis.Bile acids(BAs),produced by the liver,are the most represented organic molecules in bile.The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules.In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary(deriving by bacterial manipulation of primary molecules)ones.This class of BAs is demonstrated to have relevant biological effects,ranging from toxic to therapeutic ones.In this family ursodeoxycholic and lithocholic acid present the most interesting features.The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage.These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.展开更多
The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs,along with the potential mechanisms involved.Twenty-one finishing pigs(Dur...The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs,along with the potential mechanisms involved.Twenty-one finishing pigs(Duroc×Landrace×Yorkshire[DLY];average BW=144.38±8.92 kg)were assigned to three dietary treatments,with each treatment containing seven replicates,each consisting of one pig.The three dietary treatments included:a basic diet,a basic diet supplemented with 500 mg/kg of hyodeoxycholic acid(HDCA),and a basic diet supplemented with 500 mg/kg of lithocholic acid(LCA).The trial lasted for 28 d.Hyodeoxycholic acid was used in the in vitro experiments and added to mature 3T3-L1 adipocytes for 4 d to elucidate the mechanism by which bile acids regulate lipid metabolism.The results suggested that HDCA tended to decrease backfat thickness in finishing pigs(P=0.094)and reduced the size of lipid droplets in 3T3-L1 adipocytes(P=0.012),whereas LCA increased backfat thickness(P=0.016)and induced larger lipid droplets in the abdominal adipose tissue(P=0.003).Furthermore,HDCA enhanced the expression of Takeda G-protein-coupled receptor 5 protein and hormone-sensitive lipase(HSL)gene in backfat of pigs(P<0.05)and increased the protein expression of phosphorylated HSL(p-HSL)in vitro(P=0.093).Compared to HDCA,LCA addition increased the gene and protein expression of peroxisome proliferator activated receptor gamma in backfat of pigs(P<0.05)and enhanced the expression of hepatic genes sterol regulatory element-binding protein-1c and fatty acid synthase(P<0.05).In conclusion,HDCA enhanced lipolysis and partially decreased backfat thickness in finishing pigs,while LCA promoted lipid synthesis and increased backfat thickness of pigs.The variations in the effects of various bile acids on bile acid receptors could explain these functional differences.展开更多
文摘To study the effect of the toxic secondary bile acid lithocholic acid （LCA） on the expression of fibroblast growth factor 19 （FGF19） in intestinal cells and to characterize the pregnane-X-receptor （PXR） response of the FGF19 promoter region. METHODS： The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy- cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors, RESULTS： LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two poten- tial binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor （RXR） and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activ- ity in intestinal cells. CONCLUSION： LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.
文摘The dietary intervention of calorie restriction(CR)is known to have the most profound effects on healthspan and lifespan across several species.In two recent back-to-back articles published in Nature,Qu et al.[1,2]revealed that lithocholic acid(LCA),a singular secondary bile acid found to be elevated in the serum of calorie-restricted mice,is sufficient to mimic the effects of CR by delaying the onset of age-associated phenotypes in mice,and promoting lifespan extension in nematodes and flies.The authors showed that the anti-ageing effects of LCA are mediated through a conserved mechanism resulting in the activation of the lysosomal adenosine-monophosphate(AMP)-activated protein kinase(AMPK)pathway through the TUB-like protein 3(TULP3)-sirtuin(SIRT)-vacuolar H+-ATPase(v-ATPase)axis tomediate thebenefits of CR.
基金The authors would like to thank National Science Foundation(DMR-1608151).
文摘Bacterial infections have become a global issue that requires urgent attention,particularly regarding to emergence of multidrug resistant bacteria.We developed quaternary amine-containing antimicrobial poly(bile acid)s that contain a hydrophobic core of lithocholic acid in the main-chain.Interestingly,by choosing appropriate monomers,these cationic polymers can form core-shell micelles.These polymers exhibited biocidal activity against both Gram-positive and Gram-negative bacterial species.It is demonstrated that the micelles can deliver hydrophobic antibiotics that functionally have dual antimicrobial activities.Cytotoxicity assays against HeLa cells showed dosage-dependent toxicity for polymers with longer linkers.
基金Supported by Dr.Nori Tolosa de Talamoni from CONICET,No.PIP 2013-2015 and No.SECYT(UNC)2016,Argentina
文摘The disequilibrium between the production of reactive oxygen(ROS) and nitrogen(RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-products of electron transport chain. Most of the time the intestine responds adequately against the oxidative stress, but with aging or under conditions that exacerbate the ROS and/or RNS production, the defenses are not enough and contribute to developing intestinal pathologies. The endogenous antioxidant defense system in gut includes glutathione(GSH) and GSH-dependent enzymes as major components. When the ROS and/or RNS production is exacerbated, oxidative stress occurs and the intestinal Ca2+ absorption is inhibited. GSH depleting drugs such as DLbuthionine-S,R-sulfoximine, menadione and sodium deoxycholate inhibit the Ca2+ transport from lumen to blood by alteration in the protein expression and/or activity of molecules involved in the Ca2+ transcellular and paracellular pathways through mechanisms of oxidative stress, apoptosis and/or autophagy. Quercetin, melatonin, lithocholic and ursodeoxycholic acids block the effect of those drugs in experimental animals by their antioxidant, anti-apoptotic and/or anti-autophagic properties. Therefore, they may become drugs of choice for treatment of deteriorated intestinal Ca2+ absorption under oxidant conditions such as aging, diabetes, gut inflammation and other intestinal disorders.
文摘The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocytes)in bile formation.The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases,such as primary biliary cholangitis or primary sclerosing cholangitis.Bile acids(BAs),produced by the liver,are the most represented organic molecules in bile.The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules.In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary(deriving by bacterial manipulation of primary molecules)ones.This class of BAs is demonstrated to have relevant biological effects,ranging from toxic to therapeutic ones.In this family ursodeoxycholic and lithocholic acid present the most interesting features.The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage.These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.
基金Funding for this research was provided by the National Natural Science Foundation of China under grant number 31730091.
文摘The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs,along with the potential mechanisms involved.Twenty-one finishing pigs(Duroc×Landrace×Yorkshire[DLY];average BW=144.38±8.92 kg)were assigned to three dietary treatments,with each treatment containing seven replicates,each consisting of one pig.The three dietary treatments included:a basic diet,a basic diet supplemented with 500 mg/kg of hyodeoxycholic acid(HDCA),and a basic diet supplemented with 500 mg/kg of lithocholic acid(LCA).The trial lasted for 28 d.Hyodeoxycholic acid was used in the in vitro experiments and added to mature 3T3-L1 adipocytes for 4 d to elucidate the mechanism by which bile acids regulate lipid metabolism.The results suggested that HDCA tended to decrease backfat thickness in finishing pigs(P=0.094)and reduced the size of lipid droplets in 3T3-L1 adipocytes(P=0.012),whereas LCA increased backfat thickness(P=0.016)and induced larger lipid droplets in the abdominal adipose tissue(P=0.003).Furthermore,HDCA enhanced the expression of Takeda G-protein-coupled receptor 5 protein and hormone-sensitive lipase(HSL)gene in backfat of pigs(P<0.05)and increased the protein expression of phosphorylated HSL(p-HSL)in vitro(P=0.093).Compared to HDCA,LCA addition increased the gene and protein expression of peroxisome proliferator activated receptor gamma in backfat of pigs(P<0.05)and enhanced the expression of hepatic genes sterol regulatory element-binding protein-1c and fatty acid synthase(P<0.05).In conclusion,HDCA enhanced lipolysis and partially decreased backfat thickness in finishing pigs,while LCA promoted lipid synthesis and increased backfat thickness of pigs.The variations in the effects of various bile acids on bile acid receptors could explain these functional differences.
