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

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.

Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury

“…This was also evident in Cyp2c70 - Cyp2a12 double KO mice, where UDCA feeding improved neonatal viability and was protective in the male and female double KO mice at 6 weeks of age and in male double KO mice at 20 weeks of age. ( 59 ). In contrast, UDCA-treated female Cyp2c70 - Cyp2a12 double KO mice at 20 weeks of age still exhibited significant liver injury, with a greatly elevated hepatic BA content and taurolithocholic acid–enriched hydrophobic BA composition ( 59 ).…”

“…( 59 ). In contrast, UDCA-treated female Cyp2c70 - Cyp2a12 double KO mice at 20 weeks of age still exhibited significant liver injury, with a greatly elevated hepatic BA content and taurolithocholic acid–enriched hydrophobic BA composition ( 59 ). When the steroidal farnesoid X-receptor agonist obeticholic acid was recently evaluated in Cyp2c70 KO mice, short-term 4-weeks treatment did not improve the hepatic fibrosis or development of cholangiopathy, despite suppressing BA synthesis ( 60 ).…”

Using Multidimensional Separations to Distinguish Isomeric Amino Acid–Bile Acid Conjugates and Assess Their Presence and Perturbations in Model Systems

“…While CA conjugates were conserved in both mouse cecal and human stool extracts, MCA conjugates were not observed in the human FMT samples. 34,35 Hierarchical clustering and PCA for FMT experiments (Figures 5A,B and S9) noted decreased temporal resolution for each sampling period in contrast to the mouse data, though the timespan for FMT sample collection is notably longer (months) versus the mouse model (weeks). Hierarchical clustering results showed that CA and CDCA conjugates are present pre-FMT and depleted in post-FMT, while DCA and related conjugates showed the opposite trend.…”

Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice

“…Moreover, CDCA is metabolized into muricholic acids in mice which are absent in humans and have different affinities for bile acid receptors compared to CDCA and lithocholic acid, a CDCA-derived secondary bile acid. Knockout mouse models that lack the bile acid metabolizing enzymes Cyp2c70/Cyp2a12 have bile acid pools closer to humans 30, 31 . Future studies utilizing these models could help elucidate the physiological impact of I3A on liver bile acids and their role in fatty liver disease.…”

“…Knockout mouse models that lack the bile acid metabolizing enzymes Cyp2c70/Cyp2a12 have bile acid pools closer to humans 30,31 . Future studies utilizing these models could help elucidate the physiological impact of I3A on liver bile acids and their role in fatty liver disease.…”