Bile acids and their receptors: modulators and therapeutic targets in liver inflammation

Bertolini, Anna; Fiorotto, Romina; Strazzabosco, Mario

doi:10.1007/s00281-022-00935-7

Cited by 46 publications

(25 citation statements)

References 203 publications

(223 reference statements)

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“…Indeed, the latter are also ligands for receptors that include the nuclear receptor farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor 1 (or TGR5). These receptors regulate host basal metabolism and enterohepatic circulation [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

et al. 2022

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Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in the gallbladder, help the absorption/processing of lipids, and modulate host inflammatory responses and gut microbiota (GM) composition. The latter is the new “actor” that links the GI tract and liver in NAFLD pathogenesis. In fact, the discovery and mechanistic characterization of hepatic and intestinal farnesoid X receptor (FXR) shed new light on the gut–liver axis. We conducted a search on the main medical databases for original articles, reviews, meta-analyses of randomized clinical trials, and case series using the following keywords, their acronyms, and their associations: farnesoid X receptor, bile acids metabolism, gut microbiota, dysbiosis, and liver steatosis. Findings on the synthesis, metabolism, and conjugation processes of BAs, and their action on FXR, change the understanding of NAFLD physiopathology. In detail, BAs act as ligands to several FXRs with GM modulation. On the other hand, the BAs pool is modulated by GM, thus, regulating FXRs functioning in the frame of liver fat deposition and fibrosis development. In conclusion, BAs passed from their role of simple lipid absorption and metabolism agents to messengers between the gut and liver, modulated by GM.

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Section: Resultsmentioning

confidence: 99%

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

et al. 2022

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“…In general, data on the efficacy of the new therapeutic agents are still undergoing investigation in clinical trials and are too premature to provide practical information to physicians. The crucial point when designing clinical trials is the choice of a combination treatment with nuclear receptor ligands and other agents with different mechanism and therapeutic effects [ 89 ]. This huge armamentarium of new therapeutic options will likely lead to a novel treatment landscape for PBC in the near future, with novel therapies based on the combinations of multiple agents acting on different pathogenetic mechanisms [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

Update on the Pharmacological Treatment of Primary Biliary Cholangitis

2022

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Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to be effective in ameliorating biochemistry alteration and symptoms typical of PBC. Moreover, a variety of new agents, acting with different mechanisms of action, are under clinical evaluation for PBC treatment, including PPAR agonists, anti-NOX agents, immunomodulators, and mesenchymal stem cell transplantation. Since an insufficient amount of data is currently available about the effect of these novel approaches on robust clinical endpoints, such as transplant-free survival, their clinical approval needs to be supported by the consistent improvement of these parameters. The intensive research in this field will hopefully lead to a novel treatment landscape for PBC in the near future, with innovative therapies based on the combination of multiple agents acting on different pathogenetic mechanisms.

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“…Among the seven bile acids used in this study, CDCA and DCA exert much stronger activation on TGR5 and FXR than the other derivatives [ 42 , 43 ]. Thus, the stimulatory roles of the two double α-hydroxy type BAs in hepatic SPX expression may be due to their greater activation potency of FXR and TGR5 [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms for Bile Acids CDCA- and DCA-Stimulated Hepatic Spexin Expression

Lai

Bai

et al. 2022

Cells

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Spexin (SPX) is a novel peptide involved in glucose and lipid metabolism and suppresses hepatic total bile acid levels by inhibiting hepatic cholesterol 7α-hydroxylase 1 expression. As important mediators for glycolysis/gluconeogenesis and lipid metabolism, the effects of bile acids on SPX expression is yet to be understood. By using SMMC7721 and BEL-7402 cell lines, we screened the effects of bile acids and found that chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) can stimulate SPX gene transcription. Both CDCA and DCA were able to stimulate SPX mRNA expression in the liver but not colon and ileum in mice. In SMMC7721 and BEL-7402 cells, CDCA- and DCA-induced SPX promoter activity was mimicked by bile acid receptor FXR and TGR5 activation and suppressed by FXR and TGR5 silencing. Adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP) activators significantly increased SPX promoter activity whereas the inhibitors for AC/CAMP/protein kinase A (PKA) and mitogen-activated protein kinases (MAPK) pathway attenuated CDCA- and DCA-induced SPX transcription. Thus, CDCA and DCA stimulate SPX expression at the hepatic level through FXR and TGR5 mediated AC/cAMP/PKA and MAPK cascades.

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Bile acids and their receptors: modulators and therapeutic targets in liver inflammation

Cited by 46 publications

References 203 publications

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

Update on the Pharmacological Treatment of Primary Biliary Cholangitis

Mechanisms for Bile Acids CDCA- and DCA-Stimulated Hepatic Spexin Expression

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