Role of bile acids in inflammatory liver diseases

AbstractBile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

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Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00223.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. G554-G573 ◽

Cited By ~ 13

Author(s):

John Y. L. Chiang ◽

Jessica M. Ferrell

Keyword(s):

Bile Acid ◽

Fatty Liver ◽

Bile Acids ◽

G Protein ◽

Liver Diseases ◽

Metabolic Diseases ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Acid Receptors ◽

G Protein Coupled

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.

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Role of Bile Acids in Dysbiosis and Treatment of Nonalcoholic Fatty Liver Disease

Mediators of Inflammation ◽

10.1155/2019/7659509 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Caihua Wang ◽

Chunpeng Zhu ◽

Liming Shao ◽

Jun Ye ◽

Yimin Shen ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Bile Acids ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Bile Acid Receptors

Nonalcoholic fatty liver disease (NAFLD) is a major health threat around the world and is characterized by dysbiosis. Primary bile acids are synthesized in the liver and converted into secondary bile acids by gut microbiota. Recent studies support the role of bile acids in modulating dysbiosis and NAFLD, while the mechanisms are not well elucidated. Dysbiosis may alter the size and the composition of the bile acid pool, resulting in reduced signaling of bile acid receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). These receptors are essential in lipid and glucose metabolism, and impaired bile acid signaling may cause NAFLD. Bile acids also reciprocally regulate the gut microbiota directly via antibacterial activity and indirectly via FXR. Therefore, bile acid signaling is closely linked to dysbiosis and NAFLD. During the past decade, stimulation of bile acid receptors with their agonists has been extensively explored for the treatment of NAFLD in both animal models and clinical trials. Early evidence has suggested the potential of bile acid receptor agonists in NAFLD management, but their long-term safety and effectiveness need further clarification.

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Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

Digestive Diseases ◽

10.1159/000450907 ◽

2017 ◽

Vol 35 (3) ◽

pp. 169-177 ◽

Cited By ~ 36

Author(s):

Susan A. Joyce ◽

Cormac G.M. Gahan

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Bile Acids ◽

Farnesoid X Receptor ◽

Gastrointestinal Microbiota ◽

Signalling Molecules ◽

Disease States ◽

Irritable Bowel ◽

Bile Acid Profiles ◽

Bile Acid Receptors

The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.

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Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules

Pharmacological Research ◽

10.1016/j.phrs.2015.12.007 ◽

2016 ◽

Vol 104 ◽

pp. 9-21 ◽

Cited By ~ 94

Author(s):

Bryan L. Copple ◽

Tiangang Li

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Signaling Molecules ◽

Bile Acid Receptors ◽

Complex Signaling

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FRI-107-Emerging role of taurine conjugated bile acids in the gut liver axis and on hepatic bile acid receptors in chronic hepatitis C

Journal of Hepatology ◽

10.1016/s0618-8278(19)30852-7 ◽

2019 ◽

Vol 70 (1) ◽

pp. e434-e435

Author(s):

Rabab Oun Ali Anwar Ali ◽

Gabriella quinn ◽

kareen hill ◽

Grace Zhang ◽

Christopher Koh ◽

...

Keyword(s):

Chronic Hepatitis ◽

Bile Acid ◽

Hepatitis C ◽

Bile Acids ◽

Chronic Hepatitis C ◽

Hepatic Bile ◽

Bile Acid Receptors ◽

Conjugated Bile Acids

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Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1

Biochemical Journal ◽

10.1042/bj20110022 ◽

2011 ◽

Vol 436 (3) ◽

pp. 621-629 ◽

Cited By ~ 28

Author(s):

Alex Odermatt ◽

Thierry Da Cunha ◽

Carlos A. Penno ◽

Charlie Chandsawangbhuwana ◽

Christian Reichert ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Human Liver ◽

Liver Microsomes ◽

Three Dimensional ◽

Hydroxysteroid Dehydrogenase ◽

Binding Mode ◽

Bile Acid Metabolism ◽

Secondary Bile Acid ◽

Micro Organisms

The oxidized bile acid 7-oxoLCA (7-oxolithocholic acid), formed primarily by gut micro-organisms, is reduced in human liver to CDCA (chenodeoxycholic acid) and, to a lesser extent, UDCA (ursodeoxycholic acid). The enzyme(s) responsible remained unknown. Using human liver microsomes, we observed enhanced 7-oxoLCA reduction in the presence of detergent. The reaction was dependent on NADPH and stimulated by glucose 6-phosphate, suggesting localization of the enzyme in the ER (endoplasmic reticulum) and dependence on NADPH-generating H6PDH (hexose-6-phosphate dehydrogenase). Using recombinant human 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1), we demonstrate efficient conversion of 7-oxoLCA into CDCA and, to a lesser extent, UDCA. Unlike the reversible metabolism of glucocorticoids, 11β-HSD1 mediated solely 7-oxo reduction of 7-oxoLCA and its taurine and glycine conjugates. Furthermore, we investigated the interference of bile acids with 11β-HSD1-dependent interconversion of glucocorticoids. 7-OxoLCA and its conjugates preferentially inhibited cortisone reduction, and CDCA and its conjugates inhibited cortisol oxidation. Three-dimensional modelling provided an explanation for the binding mode and selectivity of the bile acids studied. The results reveal that 11β-HSD1 is responsible for 7-oxoLCA reduction in humans, providing a further link between hepatic glucocorticoid activation and bile acid metabolism. These findings also suggest the need for animal and clinical studies to explore whether inhibition of 11β-HSD1 to reduce cortisol levels would also lead to an accumulation of 7-oxoLCA, thereby potentially affecting bile acid-mediated functions.

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