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Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease

Liver Research 2021年第3期5卷 119-141页

作者： Michele Biagioli stefano fiorucci Department of Medicine and Surgery University of PerugiaPerugiaItaly

Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors.The two best characterized receptors of this family are the nuclear receptor,farnesoid X re-ceptor(FXR)and the G protein-coupled receptor,G protein-coupled bile acid receptor 1(GPBAR1).FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism,energy balance,autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders.Clinical trials in non-alcoholic fatty liver disease(NAFLD),however,have shown that selective FXR agonists cause side effects while their efficacy is partial.Because FXR and GPBAR1 exert additive effects,dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials.Here,we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.

关键词： Bile acid Farnesoid X receptor(FXR) G protein-coupled bile acid receptor 1(GPBAR1) Immunity Lipid metabolism Non-alcoholic fatty liver disease(NAFLD) Non-alcoholic steatohepatitis(NASH)

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Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation

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World Journal of Gastroenterology 2009年第17期15卷 2097-2108页

作者： Barbara Renga Andrea Mencarelli Marco Migliorati Eleonora Distrutti stefano fiorucci Department of Clinical and Experimental Medicine University of Perugia Via E dal Pozzo 06122 Perugia Italy Azienda Ospedaliera di Perugia Ospedale Santa Maria della Misericordia 06122 Perugia Italy

AIM: To investigate whether the farnesoid X receptor (FXR) regulates expression of liver cystathionase (CSE), a gene involved in hydrogen sulfi de (H2S) generation. METHODS: The regulation of CSE expression in response to FXR ligands was evaluated in HepG2 cells and in wild-type and FXR null mice treated with 6-ethyl chenodeoxycholic acid (6E-CDCA), a synthetic FXR ligand. The analysis demonstrated an FXR responsive element in the 5'-flanking region of the human CSE gene. The function of this site was investigated by luciferase reporter assays, chromatin immunoprecipitation and electrophoretic mobility shift assays. Livers obtained from rats treated with carbon tetrachloride alone, or in combination with 6-ethyl chenodeoxycholic acid, were studied for hydrogen sulphide generation and portal pressure measurement. RESULTS: Liver expression of CSE is regulated by bile acids by means of an FXR-mediated mechanism. Western blotting, qualitative and quantitative polymerase chain reaction, as well as immunohistochemical analysis, showed that expression of CSE in HepG2 cells and in mice is induced by treatment with an FXR ligand. Administration of 6E-CDCA to carbon tetrachloride treated rats protected against the down-regulation of CSE expression, increased H2S generation, reduced portal pressure and attenuated the endothelial dysfunction of isolated and perfused cirrhotic rat livers. CONCLUSION: These results demonstrate that CSE is an FXR-regulated gene and provide a new molecular explanation for the pathophysiology of portal hypertension.

关键词：肝脏微循环受体调节硫化氢胆汁酸 HepG2细胞定量聚合酶链反应免疫组织化学分析鹅去氧胆酸

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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 homeostasis.Dysregulation of bile acid meta-bolism causes dysbiosis leading to obesity,diabetes,and liver-related diseases.Bile 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

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Gut microbiota role in irritable bowel syndrome:Newtherapeutic strategies

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World Journal of Gastroenterology 2016年第7期22卷 2219-2241页

作者： Eleonora Distrutti Lorenzo Monaldi Patrizia Ricci stefano fiorucci S.C.di Gastroenterologia ed Epatologia Azienda Ospedaliera di Perugia06100 PerugiaItaly Dipartimento di Scienze Chirurgiche e Biomediche Universitàdegli Studi di Perugia06100 PerugiaItaly

In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome(IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial(Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful(Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required.

关键词： Irritable bowel syndrome Gut microbiota Probiotics Prebiotics Synbiotics Antibiotics Fecaltransplantation

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