Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways inv...Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs.BAs regulate their own homeostasis via signaling pathways.BAs also affect diverse metabolic pathways including glucose metabolism,lipid metabolism and energy expenditure.This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.展开更多
Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produce...Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produces primary BAs,the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions.Mechanistically,BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors.Disruption of BA transport and homeostasis leads to the progression of liver diseases,including metabolic dysfunction-associated steatotic liver disease(MASLD)and hepatocellular carcinoma(HCC).Here,we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.展开更多
Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasi...Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasis.Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome,while gut microbes influence the composition of the circulating bile acid pool.Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself.This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis,as well as their function as mediators of cellular signaling in the liver-gut-brain axis.展开更多
Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea an...Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.展开更多
Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Take...Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.展开更多
Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regula...Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor(Fxr)and the membrane receptor Takeda G protein-coupled receptor 5(Tgr5).Tgr5 is highly expressed in the gut and skeletal muscle,and in cholangiocytes and Kupffer cells of the liver.Tgr5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy homeostasis.Here,we used a high fat,high fructose,and high sucrose(HFS)diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis.Materials and methods:Female C57BL/6J control wild type(WT)and Tgr5 knockout(Tgr5^(-/-))mice were fed HFS(high fat(40%kcal),high fructose,and 20%sucrose water)diet for 20 weeks.Metabolic phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation pathways.Results:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT mice.Tgr5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly upregulated.Hepatic cholesterol 7alpha-hydroxylase(Cyp7a1)gene expression was consistently elevated in Tgr5^(-/-)mice,while oxysterol 7alpha-hydroxylase(Cyp7b1),sterol 27-hydroxylase(Cyp27a1),Fxr,and small heterodimer partner(Shp)were downregulated by HFS diet.Surprisingly,hepatic inflammation and fibrosis were also significantly reduced in Tgr5^(-/-)mice fed HFS diet,which may be due to altered se-rotonin signaling in the liver.Conclusions:Tgr5^(-/-)mice may be protected from high fat,high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.展开更多
文摘Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs.BAs regulate their own homeostasis via signaling pathways.BAs also affect diverse metabolic pathways including glucose metabolism,lipid metabolism and energy expenditure.This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.
基金supported by the National Natural Science Foundation of China(No.82130022,31925021)the National Key Research and Development Program of China(No.2018YFA0800700 and 2022YFC3401500).
文摘Bile acids(BAs)play important roles in the digestion of dietary fats and molecular signal transduction,and modulation of the BA composition usually affects the progression of metabolic diseases.While the liver produces primary BAs,the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions.Mechanistically,BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors.Disruption of BA transport and homeostasis leads to the progression of liver diseases,including metabolic dysfunction-associated steatotic liver disease(MASLD)and hepatocellular carcinoma(HCC).Here,we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.
基金This work was supported by the USA National Institutes of Health AA015951 to J.M.Ferrell,and DK44442 and DK58379 to J.Y.L.Chiang.
文摘Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient ab-sorption,and they play roles in glucose,lipid,and energy metabolism and in gut microbiome and metabolic homeostasis.Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome,while gut microbes influence the composition of the circulating bile acid pool.Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself.This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis,as well as their function as mediators of cellular signaling in the liver-gut-brain axis.
基金The work in the authors'laboratories was supported by merit review grants from the Department of Veterans Affairs,United States(VA):BX000152(W.A.Alrefai)and BX002011(P.K.Dudeja)F30 grant DK117535(A.L.Ticho)and R01 grants:DK109709(W.A.Alrefai),DK54016(P.K.Dudeja),DK81858(P.K.Dudeja),DK92441(P.K.Dudeja),DK98170(R.K.Gill),from the USA National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health,United States.
文摘Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.
基金This study was supported by grants funded by the USA National Institutes of Health(NIH)U01CA179582 and R01 CA222490.
文摘Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.
基金This work was supported by the USA National Institutes of Health(NIH)(AA015951,DK044442,and DK058379).
文摘Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor(Fxr)and the membrane receptor Takeda G protein-coupled receptor 5(Tgr5).Tgr5 is highly expressed in the gut and skeletal muscle,and in cholangiocytes and Kupffer cells of the liver.Tgr5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy homeostasis.Here,we used a high fat,high fructose,and high sucrose(HFS)diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis.Materials and methods:Female C57BL/6J control wild type(WT)and Tgr5 knockout(Tgr5^(-/-))mice were fed HFS(high fat(40%kcal),high fructose,and 20%sucrose water)diet for 20 weeks.Metabolic phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation pathways.Results:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT mice.Tgr5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly upregulated.Hepatic cholesterol 7alpha-hydroxylase(Cyp7a1)gene expression was consistently elevated in Tgr5^(-/-)mice,while oxysterol 7alpha-hydroxylase(Cyp7b1),sterol 27-hydroxylase(Cyp27a1),Fxr,and small heterodimer partner(Shp)were downregulated by HFS diet.Surprisingly,hepatic inflammation and fibrosis were also significantly reduced in Tgr5^(-/-)mice fed HFS diet,which may be due to altered se-rotonin signaling in the liver.Conclusions:Tgr5^(-/-)mice may be protected from high fat,high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.
