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

Wang, Yifeng; Li, Jibiao; Matye, David J.; Zhang, Yuxia; Dennis, Katie; Ding, Wen–Xing; Li, Tiangang

doi:10.1172/jci.insight.99676

Cited by 43 publications

(30 citation statements)

References 59 publications

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“…Finally, the changes in synthesis of taurine and GSH could have been related to bile acid metabolism. In mice, when bile acid recycling was disrupted, changes in hepatic CDO, CSAD, GCL, and metabolites indicated that GSH production was decreased, whereas taurine increased (Wang et al, 2018). Although bile acid recycling itself was not measured in the present study, a possibility exists that this process was inhibited by choline during NNB, which resulted in enhanced taurine rather than GSH synthesis.…”

Section: Transsulfuration Pathwaymentioning

confidence: 63%

Choline supply during negative nutrient balance alters hepatic cystathionine β-synthase, intermediates of the methionine cycle and transsulfuration pathway, and liver function in Holstein cows

Coleman

Alharthi

Lopreiato

et al. 2019

Journal of Dairy Science

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Although choline requirements for cows are unknown, enhanced postruminal supply may decrease liver triacylglycerol and increase flux through the Met cycle to improve immunometabolic status during a negative nutrient balance (NNB). Our objectives were to investigate the effects of postruminal choline supply during a feed restriction-induced NNB on (1) hepatic activity cystathionine β-synthase and transcription of enzymes in the transsulfuration pathway and Met cycle; (2) hepatic metabolites in the Met cycle and the transsulfuration pathway, bile acids, and energy metabolism; and 3) plasma biomarkers of liver function, inflammation, and oxidative stress. Ten primiparous rumencannulated Holstein cows (158 ± 24 d postpartum) were used in a replicated 5 × 5 Latin square design with 4-d treatment periods and 10 d of recovery (14 d/period). Treatments were unrestricted intake with abomasal infusion of water, restricted intake (R; 60% of net energy for lactation requirements) with abomasal infusion of water, or R plus abomasal infusion of 6.25, 12.5, or 25 g/d choline ion. Liver tissue was collected on d 5 after infusions ended, and blood was collected on d 1, 3, and 5. Statistical contrasts were A0 versus R0 (CONT1), R versus the average of choline doses (CONT2), and tests of linear and quadratic effects of choline dose. Activity of cystathionine β-synthase was lower with R (CONT1) and decreased linearly with choline. Hepatic glutathione was not different with R or choline, but taurine tended to be greater with choline (CONT2). Betaine and carnitine were greater with R (CONT1) and further increased with choline (CONT2). Concentrations of NAD + were greater with choline (CONT2). Cholic and glycol-chenodeoxycholic acids were decreased by R and choline, while taurocholic and tauro-chenodeoxycholic acids were not altered. Plasma aspartate aminotransferase and bilirubin were greater with R (CONT1) but decreased with choline (CONT2). Paraoxonase was lower with R and increased with choline (CONT2). Data suggest that enhanced supply of choline during NNB decreases entry of homocysteine to the transsulfuration pathway, potentially favoring remethylation to Met by acquiring a methyl group from betaine. As such, Met may provide methyl groups for synthesis of carnitine. Along with production data indicating that 12.5 g/d choline ion improved milk yield and liver fatty acid metabolism during NNB, the changes in blood biomarkers also suggest a beneficial effect of choline supply on liver function and oxidative stress.

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Section: Transsulfuration Pathwaymentioning

confidence: 63%

Choline supply during negative nutrient balance alters hepatic cystathionine β-synthase, intermediates of the methionine cycle and transsulfuration pathway, and liver function in Holstein cows

Coleman

Alharthi

Lopreiato

et al. 2019

Journal of Dairy Science

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“…Concentrations of non-conjugated bile acids were observed to be altered in AD in human blood and brain samples and in transgenic models of the disease 58 , 63 . A recent study on mouse models discovered that bile acids strongly inhibit the cysteine dioxygenase type-1-mediated (CDO1-mediated) cysteine catabolic pathway resulting in depletion of the free cysteine pool and reduction of the glutathione concentration 64 . Here, we found an increased level of taurochenodeoxycholic or taurodeoxycholic acid conjugates in AD patients.…”

Section: Discussionmentioning

confidence: 99%

Urinary metabolic phenotyping for Alzheimer’s disease

Kurbatova

Garg

Whiley

et al. 2020

Sci Rep

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Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer’s Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer’s Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer’s Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer’s Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer’s pathology in previous studies.

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“…Moreover, feeding a choline-deficient, iron-supplemented L-amino aciddefined diet to rats has been shown to induce a persistent fibrosis, potentially secondary to increased oxidative stress (51). This later observation is particularly important since it has recently been shown that interrupting the enterohepatic circulation of bile acids in mice decreases hepatic glutathione levels and impairs glutathione regenerating capacity (52). This is due in part to increased expression of cysteine dioxygenase type 1, in order to shunt cysteine toward taurine biosynthesis to meet the increased demand for synthesis of taurine-conjugated bile acids.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is a major growing worldwide health problem. We previously reported that interruption of the enterohepatic circulation of bile acids using a non-absorbable apical sodium-dependent bile acid transporter inhibitor (ASBTi; SC-435) reduced the development of NAFLD in high fat diet fed mice. However, the ability of ASBTi treatment to impact the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis in a diet-induced mouse model remains untested. In the current study, we assessed whether ASBTi treatment is hepatoprotective in the choline-deficient, L-amino acid-defined (CDAA) diet model of NASH-induced fibrosis. Methods: Male C57Bl/6 mice were fed with: (A) choline-sufficient L-amino acid-defined diet (CSAA) (31 kcal% fat), (B) CSAA diet plus ASBTi (SC-435; 60 ppm), (C) CDAA diet, or (D) CDAA diet plus ASBTi. Body weight and food intake were monitored. After 22 weeks on diet, liver histology, cholesterol and triglyceride levels, and gene expression were measured. Fecal bile acid and fat excretion were measured, and intestinal fat absorption was determined using the sucrose polybehenate method. Results: ASBTi treatment reduced bodyweight gain in mice fed either the CSAA or CDAA diet, and prevented the increase in liver to body weight ratio observed in CDAA-fed mice. ASBTi significantly reduced hepatic total cholesterol levels in both CSAA and CDAA-fed mice. ASBTi-associated significant reductions in hepatic triglyceride levels and histological scoring for NAFLD activity were observed in CSAA but not CDAAfed mice. These changes correlated with measurements of intestinal fat absorption, which was significantly reduced in ASBTi-treated mice fed the CSAA (85 vs. 94%, P < 0.001) but not CDAA diet (93 vs. 93%). As scored by Ishak staging of Sirius red stained liver sections, no hepatic fibrosis was evident in the CSAA diet mice. The CDAA diet-fed mice developed hepatic fibrosis, which was increased by the ASBTi. Rao et al. Hepatoprotective Mechanisms of ASBT Inhibition Conclusions: ASBT inhibition reduced intestinal fat absorption, bodyweight gain and hepatic steatosis in CSAA diet-fed mice. The effects of the ASBTi on steatosis and fat absorption were attenuated in the context of dietary choline-deficiency. Inhibition of intestinal absorption of fatty acids may be involved in the therapeutic effects of ASBTi treatment.

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

Cited by 43 publications

References 59 publications

Choline supply during negative nutrient balance alters hepatic cystathionine β-synthase, intermediates of the methionine cycle and transsulfuration pathway, and liver function in Holstein cows

Choline supply during negative nutrient balance alters hepatic cystathionine β-synthase, intermediates of the methionine cycle and transsulfuration pathway, and liver function in Holstein cows

Urinary metabolic phenotyping for Alzheimer’s disease

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

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