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Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis

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liver Research 2022年第4期6卷 214-226页

作者： Jessica M.Ferrell Matthew Dilts Zachary Stahl Shannon Boehme Sabita Pokhrel Xinwen Wang john y.l.chiang Department of Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOHUSA Department of Pharmaceutical Sciences Northeast Ohio Medical UniversityRootstownOHUSA

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 *** 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 ***5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy ***,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 *** 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 *** phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation ***:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT ***5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly *** 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 ***,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 ***:Tgr5^(-/-)mice may be protected from high fat,high sugar-

关键词： Non-alcoholic fatty liver disease(NAFlD) liver fibrosis Takeda G protein-coupled receptor 5(TGR5) Serotonin(5-HT) High fat,high fructose,and high sucrose (HFS)

Circadian rhythms in liver metabolism and disease

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Acta Pharmaceutica Sinica B 2015年第2期5卷 113-122页

作者： Jessica M.Ferrell john y.l.chiang Department of Integrative Medical Sciences Northeast Ohio Medical University

Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and ***, these associations are reviewed with respect to liver metabolism and disease.

关键词： Circadian rhythm liver Metabolic syndrome Type 2 diabetes

The gut's feeling on bile acid signaling in NAFlD

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Hepatobiliary Surgery and Nutrition 2018年第2期7卷 151-153页

作者： john y.l.chiang Department of Integrative Medical Sciences College of MedicineNortheast Ohio Medical UniversityRootstownOHUSA

The gut to live axis plays a critical role in regulation of hepatic bile acid synthesis and metabolic homeostasis(1).Non-alcoholic fatty liver disease(NAFlD)is the most common chronic liver disease with a high prevalence of^35%in *** can progress from simple steatosis to non-alcoholic steatohepatitis(NASH),cirrhosis and hepatocellular *** is associated with insulin resistance,obesity and type 2 *** acid-activated farnesoid X receptor(FXR)and G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5)have been shown to regulate lipid,glucose and energy metabolism and activation of FXR by agonists have been shown to improve hepatic metabolism and metabolic disorder in several mouse models of NASH(2).However,the role of bile acid signaling in pathogenesis and treatment of NASH is not clear.

关键词： NAFlD metabolism bile

Bile acid metabolism and signaling in liver disease and therapy

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liver Research 2017年第1期1卷 3-9页

作者： john y.l.chiang Department of Integrative Medical Sciences College of MedicineNortheast Ohio Medical UniversityRootstownOHUSA

Bile acids play a critical role in the regulation of glucose,lipid,and energy metabolism through activation of the nuclear bile acid receptor farnesoid X receptor(FXR)and membrane G protein-coupled bile acid receptor-1(Gpbar-1,aka TGR5).Agonist activation of FXR and TGR5 improves insulin and glucose sensitivity and stimulates energy metabolism to prevent diabetes,obesity,and non-alcoholic fatty liver disease(NAFlD).Bile acids have both pro-and anti-inflammatory actions through FXR and TGR5 in the intestine and *** the intestine,bile acids activate FXR and TGR5 to stimulate fibroblast growth factor 15 and glucagon-like peptide-1 *** and TGR5 agonists may have therapeutic potential for treating liver-related metabolic diseases,such as diabetes and NAFlD.

关键词： Bile acid metabolism Cholestatic liver diseases Metabolic diseases

Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic Iiver disease

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Hepatobiliary Surgery and Nutrition 2020年第2期9卷 152-169页

作者： Tiangang li john y.l.chiang Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA Department of Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOHUSA

Bile acids are synthesized from cholesterol only in *** acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small *** acids are signaling molecules that activate nuclear receptor farnesoid X receptor(FXR)and cell surface G protein-coupled receptor *** critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid *** addition,bile acid-activated cellular signaling pathways regulate metabolic homeostasis,immunity,and cell proliferation in various metabolically active *** the small and large intestine,gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological *** turn,bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and ***,bile acid-based therapies including systemic and intestine-restricted FXR agonists,TGR5 agonists,fibroblast growth factor 19 analogue,intestine FXR antagonists,and intestine apical sodium-bile acid transporter(ASBT)inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis(NASH).These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research *** recently,human and experimental alcoholic liver disease(AlD)has been associated with disrupted bile acid *** additional,new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating AlD.

关键词： Bile acid farnesoid X receptor(FXR) microbiota non-alcoholic steatohepatitis(NASH) alcoholic liver disease(AlD)

Bile acid receptors and signaling crosstalk in the liver, gut and brain

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liver Research 2021年第3期5卷 105-118页

作者： Jessica M.Ferrell john y.l.chiang Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOHUSA

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 *** 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 *** 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 *** 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.

关键词： Bile acid metabolism Farnesoid X receptor(FXR) Gut-brain axis Microbiome Neurodegenerative disease Takeda G protein-coupled receptor(TGR5)

Up to date on cholesterol 7 alpha-hydroxylase (CyP7A1) in bile acid synthesis

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liver Research 2020年第2期4卷 47-63页

作者： john y.l.chiang Jessica M.Ferrell Department of Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOHUSA

Cholesterol 7 alpha-hydroxylase(CyP7A1,EC1.14)is the first and rate-limiting enzyme in the classic bile acid synthesis *** 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 *** 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 *** 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.

关键词： Cholesterol 7 alpha-hydroxylase(CyP7A1) Bile acid metabolism Farnesoid X receptor(FXR) Takeda G protein-coupled receptor 5(TGR5) Bile acid receptors liver metabolism

Bile acid metabolism and bile acid receptor signaling in metabolic diseases and therapy

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liver Research 2021年第3期5卷 103-104页

作者： john y.l.chiang Stefano Fiorucci Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOHUSA Department of Medicine and Surgery University of PerugiaPerugiaItaly

Bile acids are nutrient sensors and metabolic regulators that control nutrient intake and gut bacteria growth to regulate glucose,lipid,and energy *** of bile acid meta-bolism causes dysbiosis leading to obesity,diabetes,and liver-related *** acids and their derivatives have emerged as therapeutic drugs for treating liver metabolic and cholestatic dis-eases,type 2 diabetes,and non-alcoholic steatohepatitis(NASH).This special issue covers five emerging topics in bile acid research in metabolic diseases:(i)bile acid synthesis and metabolism in liver metabolic diseases;(ii)bile acid-activated receptors and signaling in liver metabolism and diseases;(iii)gut microbiome in liver path-ophysiology and cholestasis;(iv)bile acid metabolism in metabolic gastric surgery;and(v)cholestasis-associated renal injury,disease,and therapy.

关键词： metabolism bile diseases

Bile acid metabolism and signaling in liver diseases:Emerging trends of liver research and therapy

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liver Research 2017年第1期1卷 1-2页

作者： john y.l.chiang Department of Integrative Medical Sciences College of MedicineNortheast Ohio Medical UniversityRootstownOHUSA

Conversion of cholesterol to bile acids is the only significant catabolic pathway for elimination of excessive cholesterol in our *** acids have long been recognized as important physiological agents that facilitate a... 详细信息

关键词： metabolism cholesterol vitamin