Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury
Yifeng Wang, … , Wen-Xing Ding, Tiangang Li
Yifeng Wang, … , Wen-Xing Ding, Tiangang Li
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e99676. https://doi.org/10.1172/jci.insight.99676.
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Research Article Hepatology Metabolism

Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury

Abstract

Bile acids are signaling molecules that critically control hepatocellular function. Disrupted bile acid homeostasis may be implicated in the pathogenesis of chronic liver diseases. Glutathione is an important antioxidant that protects the liver against oxidative injury. Various forms of liver disease share the common characteristics of reduced cellular glutathione and elevated oxidative stress. This study reports a potentially novel physiological function of bile acids in regulating hepatic sulfur amino acid and glutathione metabolism. We found that bile acids strongly inhibited the cysteine dioxygenase type-1–mediated (CDO1-mediated) cysteine catabolic pathway via a farnesoid X receptor–dependent mechanism. Attenuating this bile acid repressive effect depleted the free cysteine pool and reduced the glutathione concentration in mouse liver. Upon acetaminophen challenge, cholestyramine-fed mice showed impaired hepatic glutathione regeneration capacity and markedly worsened liver injury, which was fully prevented by N-acetylcysteine administration. These effects were recapitulated in CDO1-overexpressing hepatocytes. Findings from this study support the importance of maintaining bile acid homeostasis under physiological and pathophysiological conditions, as altered hepatic bile acid signaling may negatively impact the antioxidant defense mechanism and sensitivity to oxidative injury. Furthermore, this finding provides a possible explanation for the reported mild hepatotoxicity associated with the clinical use of bile acid sequestrants in human patients.

Authors

Yifeng Wang, Jibiao Li, David Matye, Yuxia Zhang, Katie Dennis, Wen-Xing Ding, Tiangang Li

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Figure 1

Disrupting enterohepatic bile acid recycling decreased hepatic glutathione in mice.

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Disrupting enterohepatic bile acid recycling decreased hepatic glutathio...
(A) Illustration of cellular cysteine and glutathione (GSH) metabolism. Cysteine can be obtained from extracellular or intracellular sources including conversion from methionine via multistep reactions. In GSH synthesis, cysteine and glutamate are used by GCL to produce γ-glutamylcysteine, which is then linked to glycine to produce GSH. GSH can be transported out of the cells where extracellular membrane-bound GGT transfers the glutamyl moiety of GSH to amino acid acceptors to produce γ–glutamyl amino acids and cysteinylglycine, which is transported into the cells for GSH regeneration. The major cysteine degradation pathway is CDO1-mediated cysteine conversion to CSA, which can be further used by downstream enzymes to produce other metabolites such as taurine, sulfate, and pyruvate. Arrows indicate increased or decreased hepatic metabolites in cholestyramine-fed (ChTM-fed) mice. CDO1, cysteine dioxygenase-1; CSA, cysteine sulfinic acid; GCL, glutamate-cysteine ligase; CSAD, cysteine sulfinic acid decarboxylase; Cys-Gly, cysteinylglycine; GGT, γ-glutamyl transferase; γ–Glu-Cys, γ-glutamyl-cysteine. (B–E) Male C57BL/6J mice at 12 weeks of age were fed a chow diet or 2% ChTM-containing chow diet for 6 days. Livers were collected after approximately 6 hours of fasting. Liver metabolites were measured by metabolomics analysis. All results are expressed as mean ± SD. n = 5. *P < 0.05 versus chow-fed mice by 2-tailed Student’s t test. AUC, peak area under the curve.