Bile acid metabolism and signaling in liver disease and therapy

Chiang, John Y.L.

doi:10.1016/j.livres.2017.05.001

Cited by 208 publications

(166 citation statements)

References 95 publications

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“…The accumulation of bile acids, especially hydrophobic bile acids, in the liver can cause inflammation, as well as hepatocyte and biliary injury [39, 40]. Therefore, bile acid accumulation in the liver may potentiate the progression of EPP-associated liver injury.…”

Section: Discussionmentioning

confidence: 99%

Liver metabolomics in a mouse model of erythropoietic protoporphyria

Wang

Sachar

Guo

et al. 2018

Biochemical Pharmacology

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Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech-mut mice. High levels of bile acids and Cer are toxic to the liver. Furthermore, we found that the major phosphatidylcholines (PC) in the liver and the ratio of total PC to PPIX in the bile were decreased in Fech-mut mice compared to wild type mice. A decrease of the ratio of PC to PPIX in the bile can potentiate the accumulation of PPIX in the liver because PC increases PPIX solubility and excretion. These metabolomic findings suggest that the accumulation of PPIX, together with the disruption of the homeostasis of bile acids, Cer, and PC, contributes to EPP-associated liver injury.

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Section: Discussionmentioning

confidence: 99%

Liver metabolomics in a mouse model of erythropoietic protoporphyria

Wang

Sachar

Guo

et al. 2018

Biochemical Pharmacology

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“…Bile acids (BAs) are signaling molecules with diverse effects on gut microbiota as well as host immunity and metabolism [8,9]. BAs are synthesized in the liver correlate with pruritus severity while cholestyramine reduces BA levels and relieves pruritus [10].…”

Section: Introductionmentioning

confidence: 99%

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

Jena

Sheng

McNeil

et al. 2019

Journal of Dermatological Science

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Background: Dietary interventions are implicated in the development of atopic dermatitis, psoriasis, and acne. Objective: To investigate the effect of diet and the bile acid (BA) receptors, such as TGR5 (Takeda G protein receptor 5) and S1PR2 (sphingosine-1-phosphate receptor 2) in the development of dermatitis. Methods: C57BL/6 mice were fed a control diet (CD) or Western diet (WD) since weaning until they were 10 months old followed by analyzing histology, gene expression, and BA profiling. Results: Mice developed dermatitis as they aged and the incidence was higher in females than males. Additionally, WD intake substantially increased the incidence of dermatitis. Cutaneous antimicrobial peptide genesS100A8, S100A9, and Defb4 were reduced in WD-fed mice, but increased when mice developed skin lesions. In addition, Tgr5 and TGR5-regulated Dio2 and Nos3 were reduced in WD intake but induced in dermatitic lesions. Trpa1 and Trpv1, which mediate itch, were also increased in dermatitic lesions. The expression of S1pr2 and genes encoding sphingosine kinases, S1P phosphatases, binding protein, and transporter were all reduced by WD intake but elevated in dermatitic lesions. Furthermore, dermatitis development increased total cutaneous BA with an altered profile, which may change TGR5 and S1PR2 activity. Moreover, supplementation with BA sequestrant cholestyramine reduced epidermal thickening as well as cutaneous inflammatory cytokines. Conclusion: In summary, activation of TGR5 and S1PR2, which regulate itch, keratinocyte proliferation, metabolism, and inflammation, may contribute to WD-exacerbated dermatitis with Th2 and Th17 features. In addition, elevated total BA play a significant role in inducing dermatitis and cutaneous inflammation.

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“…Bile acid (BA) homeostasis is tightly controlled to prevent the toxicity of BAs without affecting their physiological functions (Chiang, ). BA homeostasis is the net effect of the interaction between BA synthesis, metabolism and disposition in both liver and intestine.…”

Section: Introductionmentioning

confidence: 99%

Species differences in bile acids II. Bile acid metabolism

Thakare

Alamoudi

Gautam

et al. 2018

J of Applied Toxicology

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One of the mechanisms of drug-induced liver injury (DILI) involves alterations in bile acid (BA) homeostasis and elimination, which encompass several metabolic pathways including hydroxylation, amidation, sulfation, glucuronidation and glutathione conjugation. Species differences in BA metabolism may play a major role in the failure of currently used in vitro and in vivo models to predict reliably the DILI during the early stages of drug discovery and development. We developed an in vitro cofactor-fortified liver S9 fraction model to compare the metabolic profiles of the four major BAs (cholic acid, chenodeoxycholic acid, lithocholic acid and ursodeoxycholic acid) between humans and several animal species. High- and low-resolution liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance imaging were used for the qualitative and quantitative analysis of BAs and their metabolites. Major species differences were found in the metabolism of BAs. Sulfation into 3-O-sulfates was a major pathway in human and chimpanzee (4.8%-52%) and it was a minor pathway in all other species (0.02%-14%). Amidation was primarily with glycine (62%-95%) in minipig and rabbit and it was primarily with taurine (43%-81%) in human, chimpanzee, dog, hamster, rat and mice. Hydroxylation was highest (13%-80%) in rat and mice followed by hamster, while it was lowest (1.6%-22%) in human, chimpanzee and minipig. C6-β hydroxylation was predominant (65%-95%) in rat and mice, while it was at C6-α position in minipig (36%-97%). Glucuronidation was highest in dog (10%-56%), while it was a minor pathway in all other species (<12%). The relative contribution of the various pathways involved in BA metabolism in vitro were in agreement with the observed plasma and urinary BA profiles in vivo and were able to predict and quantify the species differences in BA metabolism. In general, overall, BA metabolism in chimpanzee is most similar to human, while BA metabolism in rats and mice is most dissimilar from human.

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Bile acid metabolism and signaling in liver disease and therapy

Cited by 208 publications

References 95 publications

Liver metabolomics in a mouse model of erythropoietic protoporphyria

Liver metabolomics in a mouse model of erythropoietic protoporphyria

Long-term Western diet intake leads to dysregulated bile acid signaling and dermatitis with Th2 and Th17 pathway features in mice

Species differences in bile acids II. Bile acid metabolism

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