Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2 mice

Wang, Renxue; Sheps, Jonathan A.; Liu, Lin; Han, Jun; Chen, Patrick S. K.; Lamontagne, Jason; Wilson, Peter; Welch, Ian; Borchers, Christoph H.; Ling, Victor

doi:10.1194/jlr.m088070

Cited by 34 publications

(27 citation statements)

References 53 publications

(69 reference statements)

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“…BA signalling and BA pool composition are increasingly considered as crucial for intestine and liver pathophysiology, [14] , [15] , [16] , 24 , 25 and therapeutic strategies targeting BA and their receptors begin to emerge. 26 This is particularly true in the field of metabolic diseases such as obesity and diabetes, 17 as well as for cholestatic liver diseases.…”

Section: Discussionmentioning

confidence: 99%

TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload

et al. 2021

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Background & Aims As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload. Methods Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy. Results The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy. Conclusions BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions. Lay summary Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.

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Section: Discussionmentioning

confidence: 99%

TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload

et al. 2021

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“…31,42) Mutations in the ATP8B1 gene cause progressive familial intrahepatic cholestasis type 1 (PFIC1) with typical cholestatic symptoms, including elevated serum bile salt, bilirubin and transaminase levels, low γ-glutamyl transpeptidase levels, and intractable pruritus. 24,43,44) Groen et al have created Abcb4/Atp8b1 double-knockout mice. 31) Although the biliary phospholipid secretion in these double-knockout mice is as low as in Abcb4 knockout mice, hepatic damage in the double-knockout mice was less pronounced than that in Abcb4 knockout mice.…”

Section: Formation Of Biliary Lipid Structuresmentioning

confidence: 99%

Molecular Mechanisms for Protection of Hepatocytes against Bile Salt Cytotoxicity

Morita

Ikeda

Tsuji

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Biliary lipids consist mainly of bile salts, phospholipids and cholesterol, which form mixed micelles and vesicles. Bile salts play various physiological roles but have damaging effects on cell membranes due to their detergent properties. The cytotoxicity of bile salts on hepatocytes leads to liver injuries and is largely determined by the bile salt species, the concentrations of bile salts, phospholipids and cholesterol, and the lipid composition of cell membranes. In bile, monomers and simple micelles of bile salts coexist with mixed micelles and vesicles in dynamic equilibrium, and contribute to the cytotoxicity on hepatocytes. The ATPbinding cassette (ABC) transporter family members, ABCB11, ABCB4 and ABCG5/ABCG8, mediate the biliary secretion of bile salts, phospholipids and cholesterol, respectively. Mutations in ABCB4 result in severe cholestatic diseases, and the biliary phospholipids are necessary for the attenuation of bile salt cytotoxicity. On the other hand, cholesterol reverses the cytoprotective effects of phospholipids against bile salts. In addition, phosphatidylethanolamine N-methyltransferase increases the cell resistance to bile salts by changing the phospholipid composition and structures of the apical membranes. In this review, we focus on the molecular mechanisms for the protection of hepatocytes against bile salt cytotoxicity. Further understanding of these mechanisms will help to develop new therapeutic strategies for cholestatic liver diseases.

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“…BA signaling and BA pool composition are increasingly considered as crucial for intestine and liver pathophysiology [14,15,16,24,25], and therapeutic strategies targeting BA and their receptors begin to emerge [26]. This is particularly true in the field of metabolic diseases such as obesity and diabetes [17], as well as for cholestatic liver diseases [27].…”

Section: Discussionmentioning

confidence: 99%

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

Bidault

Merlen

Glénisson

et al. 2020

Preprint

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Backgrounds & AimsAs the bile acid (BA) pool composition is of major impact on liver pathophysiology, we studied its regulation by the BA receptor TGR5, promoting hepatoprotection against BA overload.MethodsWT, total and hepato-specific TGR5-KO, and TGR5-overexpressing mice were used in: partial and 90% extended hepatectomies (EH) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (1%)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied TGR5 impact on: BA pool composition, liver injury, regeneration and survival. Particular focus was made on gut microbiota (GM) and gallbladder (GB) function analysis. BA pool composition was analyzed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA pool was not related to BA synthesis alteration, nor to the TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and cohousing experiments. The TGR5-dependent control of GB dilatation was crucial for BA pool composition, as determined by experiments including RO treatment +/− cholecystectomy. The poor TGR5-KO post-EH survival rate, related with exacerbated peribiliary necrosis and BA overload, was improved by shifting the BA pool towards a more hydrophilic composition (CT and UDCA treatments). After either BDL or CA-enriched diet +/− cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic BA pool was correlated with an unfavorable outcome after hepatectomy.ConclusionBA pool composition is crucial for hepatoprotection in mice and humans. We point TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patients study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function and liver protection. We showed that the bile acid pool composition is crucial for optimal liver repair, not only in mice but also in human patients undergoing major hepatectomy.

show abstract

Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2 mice

Cited by 34 publications

References 53 publications

TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload

TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload

Molecular Mechanisms for Protection of Hepatocytes against Bile Salt Cytotoxicity

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

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