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 5

Disrupting gut bile acid recycling impaired hepatic glutathione regenerating capacity and sensitized mice to acetaminophen (APAP) hepatotoxicity.

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Disrupting gut bile acid recycling impaired hepatic glutathione regenera...
C57BL/6J male mice (12 weeks old) were fed a chow or a 2% cholestyramine-containing (ChTM-containing) chow diet for 6 days. Mice were fasted for 6 hours and then injected with 400 mg/kg APAP for 3 hours or 6 hours. The no-APAP control groups were injected with vehicle and sacrificed at the 3-hour time point. In some mice, 500 mg/kg N-acetylcysteine (NAC) was administered 15 minutes after APAP injection. (A) Plasma transaminases in chow or ChTM-fed mice. AST, aspartate aminotransferase; ALT, alanine aminotransferase. n = 5. (B) Representative H&E staining of liver sections (×10 magnification). Scale bar: 200 μm. (C) Plasma ALT. n = 5–7. (D) Liver phosphorylated JNK, total JNK, and cytochrome p450 2E1 (CYP2E1) protein levels. (E and F) Liver GSH and GSSG concentrations. n = 5–8. All results are expressed as mean ± SD. *P < 0.05 versus chow at the same time point and experimental condition; #P < 0.05 versus no-APAP-injected controls on the same diet; §P < 0.05 versus 6-hour APAP-injected mice on the same diet. Statistical significance was determined by 2-tailed Student’s t test (A) or 2-way ANOVA with Tukey’s post hoc test (C, E, and F).