A new study has observed that ileal bile acid transporter (IBAT) inhibition, an approved treatment for Alagille syndrome (ALGS), improved cholangiopathy and reduced liver injury in Cyp2c70 KO mice despite increasing the hepatic synthesis of bile acids (BAs).
The study, published in the Journal of Lipid Research, suggests inhibiting bile acid transporter function is a possible treatment route for ALGS.
“Despite being the subject of considerable study, the role of BAs and toxic bile in the pathogenesis of human cholestatic liver disease remains a fundamental unresolved question,” the authors wrote. “We tested whether blocking IBAT-mediated return of BAs to the liver in the enterohepatic circulation would be protective in Cyp2c70 KO mice and investigated the predicted cytotoxicity of the humanized BA pool composition.”
The research team employed Cyp2c70 KO mice with liver injury and administered an IBAT inhibitor to interrupt the enterohepatic circulation of BAs and assess the impact on liver injury.
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They found that treatment with IBAT inhibition reduced the weights of the liver and spleen in the Cyp2c70 KO mice and blocked increases in alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels, all markers of hepatic injury.
The improvements were associated with the reduced accumulation of BAs in the liver, suggesting that targeting the return of BAs to the liver via the inhibition of IBAT function might be a potential therapeutic approach for patients with liver disease such as those with ALGS.
The authors note that the hydrophobicity of BAs also plays an important role in the retention of BAs in Cyp2c70 KO mice and could be an additional component of such treatment, but the underlying mechanisms of this association will require further study.
Truong JK, Bennett AL, Klindt C, et al. Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury. J Lipid Res. Published online August 5, 2022. doi:10.1016/j.jlr.2022.100261