G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this family.As a membrane receptor,TGR5 is widely distributed in different...G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this family.As a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose homeostasis.Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and diabetes.With the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed.In this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.展开更多
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
BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profil...BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.展开更多
Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile acid, lipid and glu...Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile acid, lipid and glucose metabolism and modulate temperature and energy homeostasis. Furthermore, bile acids can not only promote cell proliferation and liver regeneration but can also induce programmed cell death. Bile acid functions are mediated through different pathways which comprise the activation of nuclear hormone receptors, of intracefular kinases and of the plasma membranebound, G-protein coupled bile acid receptor TGRS/Gpbar-1.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
Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as ...Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders.We have identified notoginsenoside Ftl(Ftl) from Panax notoginseng as an agonist of TGR5 in vitro.However,the pharmacological effects of Ftl on diet-induced obese(DIO) mice and the underlying mechanisms are still elusive.Here we show that Ftl(100 mg/100 diet) increased adipose lipolysis,promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1(GLP-1) secretion in the ileum of wild type but not Tgr5^(-/-) obese mice.In addition,Ftl elevated serum free and taurineconjugated bile acids(BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues.The metabolic benefits of Ftl were abolished in Cyp27 al^(-/-) mice which have much lower BA levels.These results identify Ftl as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.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
Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene...Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene expression and the underlying molecular mechanisms of bile acid feedback regulation of CYP7A1 and bile acid synthesis in the last three decades.Discovery of bile acid-activated receptors and their roles in the regulation of lipid,glucose and energy metabolism have been translated to the development of bile acid-based drug therapies for the treatment of liver-related metabolic diseases such as alcoholic and non-alcoholic fatty liver diseases,liver cirrhosis,diabetes,obesity and hepatocellular carcinoma.This review will provide an update on the advances in our understanding of the molecular biology and mechanistic insights of the regulation of CYP7A1 in bile acid synthesis in the last 40 years.展开更多
The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such...The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such as Roux-en-Y gastric bypass(RYGB)and vertical sleeve gastrectomy(VSG),currently provide the most effective treatment for obesity and type 2 diabetes(T2D),as well as for non-alcoholic steatohepatitis(NASH).However,the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive.Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery.This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor(FXR)and G protein-coupled bile acid receptor 5(TGR5)in bariatric surgery.We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.展开更多
The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and s...The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and sustainable treatments for obesity,type 2 diabetes,non-alcoholic steatohepatitis,as well as other metabolic diseases.However,the invasive nature of the surgeries limits their broad ap-plications to the general public.Therefore,developing alternative non-invasive approaches to mimic metabolic surgery is an important direction of the field.Recent studies have identified several potential metabolic surgery-induced downstream endocrine mediators,among which bile acids are key candidate signaling molecules.Bile acids are profoundly altered by metabolic surgery,which contributes to the metabolic effects of the surgery.In this review,we focus on the most recent studies on the roles of bile acids and bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor 5 in mediating the metabolic effects of metabolic surgery.We conclude that targeting bile acid pathways may be a promising pharmacological approach to mimic the beneficial effects of metabolic surgery.展开更多
Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities...Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.展开更多
基金supported by the Science and Technology Program of Guangzhou,China(No.202103000089)the Guangdong Demonstration Base for Joint Cultivation of Postgraduates(2019,China)the Science Foundation for Distinguished Young Scholars of Guangdong(2020B1515020026,China).
文摘G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this family.As a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose homeostasis.Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and diabetes.With the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed.In this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.
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 National Key Technology Support Program during“12th Five-Year Plan”Period of China,No.2014BAI08B00National Key Research and Development Plan for Precision Medicine Research,No.2017YFC0910002and Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008.
文摘BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.
文摘Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile acid, lipid and glucose metabolism and modulate temperature and energy homeostasis. Furthermore, bile acids can not only promote cell proliferation and liver regeneration but can also induce programmed cell death. Bile acid functions are mediated through different pathways which comprise the activation of nuclear hormone receptors, of intracefular kinases and of the plasma membranebound, G-protein coupled bile acid receptor TGRS/Gpbar-1.
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financially sponsored by Shanghai Pujiang Program(17PJ1408800,China)the Natural Science Foundations of China to Lili Ding(81773961)+6 种基金Zhengtao Wang(81920108033)Yingbo Yang(81703682)financially supported by the National S&T Major Special Projects of China(No.2017ZX09309006)to Li YangInterdisciplinary Program of Shanghai Jiao Tong University to Qiaoling Yang(YG2019QNA03,China)partially supported by R01DK124627George Schaeffer fundJohn Hench fund(USA)to Wendong Huang。
文摘Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders.We have identified notoginsenoside Ftl(Ftl) from Panax notoginseng as an agonist of TGR5 in vitro.However,the pharmacological effects of Ftl on diet-induced obese(DIO) mice and the underlying mechanisms are still elusive.Here we show that Ftl(100 mg/100 diet) increased adipose lipolysis,promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1(GLP-1) secretion in the ileum of wild type but not Tgr5^(-/-) obese mice.In addition,Ftl elevated serum free and taurineconjugated bile acids(BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues.The metabolic benefits of Ftl were abolished in Cyp27 al^(-/-) mice which have much lower BA levels.These results identify Ftl as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.
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 research is supported by grants DK58379 and DK44442 from the USA National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health.
文摘Cholesterol 7 alpha-hydroxylase(CYP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis pathway.Much progress has been made in understanding the transcriptional regulation of CYP7A1 gene expression and the underlying molecular mechanisms of bile acid feedback regulation of CYP7A1 and bile acid synthesis in the last three decades.Discovery of bile acid-activated receptors and their roles in the regulation of lipid,glucose and energy metabolism have been translated to the development of bile acid-based drug therapies for the treatment of liver-related metabolic diseases such as alcoholic and non-alcoholic fatty liver diseases,liver cirrhosis,diabetes,obesity and hepatocellular carcinoma.This review will provide an update on the advances in our understanding of the molecular biology and mechanistic insights of the regulation of CYP7A1 in bile acid synthesis in the last 40 years.
基金This workwas supported by the National Cancer Institute 2R01CA139158,John Hench Foundation,George Schaeffer Foundation,Chinese National Natural Science Foundation(81270935)Transform Medicine Innovation Foundation of Shanghai Jiao Tong University School of Medicine(15ZH2001)+1 种基金Research Project Funded by the Shanghai Municipal Health Bureau(20114301)the Fund of the Key Laboratory of Stem Cell Biology of Chinese Academy of Sciences(201601).
文摘The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications.Bariatric surgical procedures,such as Roux-en-Y gastric bypass(RYGB)and vertical sleeve gastrectomy(VSG),currently provide the most effective treatment for obesity and type 2 diabetes(T2D),as well as for non-alcoholic steatohepatitis(NASH).However,the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive.Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery.This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor(FXR)and G protein-coupled bile acid receptor 5(TGR5)in bariatric surgery.We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.
基金This work was supported by the National Natural Science Foundation of China(81773961)to L.Ding,along with grants from John Hench foundation,George Schaeffer foundation and National Institute of Diabetes and Digestive and Kidney Diseases(R01DK124627)to W.Huang.
文摘The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and sustainable treatments for obesity,type 2 diabetes,non-alcoholic steatohepatitis,as well as other metabolic diseases.However,the invasive nature of the surgeries limits their broad ap-plications to the general public.Therefore,developing alternative non-invasive approaches to mimic metabolic surgery is an important direction of the field.Recent studies have identified several potential metabolic surgery-induced downstream endocrine mediators,among which bile acids are key candidate signaling molecules.Bile acids are profoundly altered by metabolic surgery,which contributes to the metabolic effects of the surgery.In this review,we focus on the most recent studies on the roles of bile acids and bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor 5 in mediating the metabolic effects of metabolic surgery.We conclude that targeting bile acid pathways may be a promising pharmacological approach to mimic the beneficial effects of metabolic surgery.
基金the USA National Institutes of Health(NIH)R01CA222490.
文摘Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.
