ArticlePloS one2022
Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition.
Article in PloS one, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 23 citations in OpenAlex.
- Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response inAmerican journal of physiology. Gastrointestinal and liver physiology · 2024Article
- Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.Pharmacological reviews · 2024Review
- Article
- Article
- Using Multidimensional Separations to Distinguish Isomeric Amino Acid-Bile Acid Conjugates and Assess Their Presence and Perturbations in Model Systems.Analytical chemistry · 2023Article
- Upregulation of Taurine Biosynthesis and Bile Acid Conjugation with Taurine through FXR in a Mouse Model with Human-like Bile Acid Composition.Metabolites · 2023Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cyp2a12-/-Cyp2c70-/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.
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