Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's com...Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.展开更多
Background Farnesoid X receptor(FXR)has been identified as a therapeutic target for metabolic dysfunction-associated steatohepatitis(MASH).Hepatic FXR is especially critical in suppressing liver inflammation.FXR agoni...Background Farnesoid X receptor(FXR)has been identified as a therapeutic target for metabolic dysfunction-associated steatohepatitis(MASH).Hepatic FXR is especially critical in suppressing liver inflammation.FXR agonism and antagonism have both proven to be beneficial in the mitigation of MASH,leading to much controversy in the field,particularly regarding FXR signalling in the gut.The objective of this study was to determine the effects of ursodeoxycholic acid(UDCA),a postulated gut FXR antagonist with liver protective effects,on the mitigation and prevention of MASH development in mice with hepatic FXR deficiency.Methods For this experiment,six-week old to eight week-old male and female liver-specific FXR knockout(FXRhep-/-)and control(FXRhep flox/flox)mice were fed either a low-fat control diet(CTL)or a MASH‘Fast Food’diet(Western diet with 21%milk fat,1.25%cholesterol and 34%sucrose)both supplemented with or without 0.1%(weight/weight;w/w)UDCA for 16 weeks.Results UDCA feeding tended to reduce alanine aminotransferase levels and decrease liver lipids in the male mice.Supplementation of UDCA showed a trend towards increased UDCA and tauroursodeoxycholic acid(TUDCA)levels in serum,liver and intestine,although the male mice displayed more than twice the amount of these bile acids compared with the female mice.CTL-UDCA feeding resulted in a significant induction of Fxr and Fgf15 mRNA expression in the ileum of the male mice.Conclusion The data strongly suggest that UDCA seems to act as an FXR agonist,especially in the ileum,which contrasts with previous reports that UDCA acts as a gut FXR antagonist.In addition,UDCA seems to be exerting liver protective effects predominantly in the male mice.展开更多
As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was...As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was around 25%in the 1990s,has been increasing year by year in recent years and has exceeded 35%in the past few years(1).The spectrum of disease includes nonalcoholic fatty liver(NAFL),characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation,and nonalcoholic steatohepatitis(NASH),which is additionally characterized by the presence of inflammation and cellular injury(2).展开更多
基金supported by the National Natural Science Foundation of China(Nos.81930109,82321005,82073926,82373946 and 82073928)the Major State Basic Research DevelopmentProgramofChina(Nos.2021YFA1301300and 2022YFA1303800)+3 种基金Overseas Expertise Introduction Project for Discipline Innovation(No.G20582017001)the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(Nos.SKLNMZZ202202 and SKLNMZZ202402)the Fundamental Research Funds for the Central Universities(No.2632023TD10)the Project Program of Basic Science Research Center Base(Pharmaceutical Science)of Yantai University(No.Y202204).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.
基金supported by the National Institutes of Health(Grants:DK137451,DK122725,ES007148,ES029258,ES020721,ES005022,GM135258)the Department of Veteran Affairs(BX002741)American Society for Pharmacology and Experimental Therapeutics(ASPET)Summer Intern Program and the Rutgers University Center for Lipid Research.
文摘Background Farnesoid X receptor(FXR)has been identified as a therapeutic target for metabolic dysfunction-associated steatohepatitis(MASH).Hepatic FXR is especially critical in suppressing liver inflammation.FXR agonism and antagonism have both proven to be beneficial in the mitigation of MASH,leading to much controversy in the field,particularly regarding FXR signalling in the gut.The objective of this study was to determine the effects of ursodeoxycholic acid(UDCA),a postulated gut FXR antagonist with liver protective effects,on the mitigation and prevention of MASH development in mice with hepatic FXR deficiency.Methods For this experiment,six-week old to eight week-old male and female liver-specific FXR knockout(FXRhep-/-)and control(FXRhep flox/flox)mice were fed either a low-fat control diet(CTL)or a MASH‘Fast Food’diet(Western diet with 21%milk fat,1.25%cholesterol and 34%sucrose)both supplemented with or without 0.1%(weight/weight;w/w)UDCA for 16 weeks.Results UDCA feeding tended to reduce alanine aminotransferase levels and decrease liver lipids in the male mice.Supplementation of UDCA showed a trend towards increased UDCA and tauroursodeoxycholic acid(TUDCA)levels in serum,liver and intestine,although the male mice displayed more than twice the amount of these bile acids compared with the female mice.CTL-UDCA feeding resulted in a significant induction of Fxr and Fgf15 mRNA expression in the ileum of the male mice.Conclusion The data strongly suggest that UDCA seems to act as an FXR agonist,especially in the ileum,which contrasts with previous reports that UDCA acts as a gut FXR antagonist.In addition,UDCA seems to be exerting liver protective effects predominantly in the male mice.
文摘As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was around 25%in the 1990s,has been increasing year by year in recent years and has exceeded 35%in the past few years(1).The spectrum of disease includes nonalcoholic fatty liver(NAFL),characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation,and nonalcoholic steatohepatitis(NASH),which is additionally characterized by the presence of inflammation and cellular injury(2).
