Related Experiment Video
Updated: Jun 13, 2025
Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice
Mohammad Nazmul Hasan1, Huaiwen Wang2, Wenyi Luo3
1Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
Abstract:
Cholestasis results from impaired bile flow that causes accumulation of hepatic bile acid and injury. Alleviating bile acid hepatobiliary toxicity is a major therapeutic goal in cholestasis. Our recent study revealed a potent anticholestasis effect of glycine-conjugated β-muricholic acid (Gly-βMCA) in Cyp2c70 knockout (KO) mice with humanized hydrophobic bile acid composition. To better understand the mechanisms and human relevance of the therapeutic benefits of Gly-βMCA, we investigated the effects of Gly-βMCA on bile acid metabolism and biliary injury in Mdr2 KO mice, a cholestasis model with a hydrophilic murine bile acid composition. Gly-βMCA significantly reduced serum alkaline phosphatase (ALP), ductular reaction, and liver cytokine expression in female mice but offered little benefits in male mice. Consistently, Gly-βMCA reduced hepatic bile acids and total bile acid pool size in female but not male mice, due to its ability to promote fecal bile acid excretion. However, the endogenous taurine-conjugated muricholic acid (T-MCA) limited the ability of Gly-βMCA to further enrich the bile acid pool with Gly-βMCA-derived T-βMCA to reduce bile acid hydrophobicity. Overall, Gly-βMCA showed diminished therapeutic efficacy in Mdr2 KO mice than Cyp2c70 KO mice, which may be due to differences in bile acid hydrophobicity and disease etiology in the two cholestasis models. These findings suggest that the benefits of Gly-βMCA are mediated by its unique pharmacokinetics, which allows for simultaneous reduction of bile acid pool size and hydrophobicity. Gly-βMCA may be a promising therapy for treating human cholestasis, despite its reduced efficacy in improving the toxicity profile of murine bile acid pool.NEW & NOTEWORTHY Gly-βMCA decreases liver injury in female but not male Mdr2 KO mice. Gly-βMCA blocks bile acid absorption to reduce bile acid pool in female Mdr2 KO mice. Gly-βMCA reduces bile acid hydrophobicity by causing T-βMCA enrichment in bile, but this therapeutic benefit was partially masked by a murine bile acid composition due to abundantly synthesized T-MCA in Mdr2 KO mice. Gly-βMCA alleviates bile acid hepatobiliary toxicity by reducing both bile acid pool size and hydrophobicity.
Insights
Glycine-conjugated β-muricholic acid (Gly-βMCA) reduced liver injury in female Mdr2 knockout mice by decreasing bile acid pool size and hydrophobicity. Its therapeutic benefits were sex-dependent and influenced by endogenous bile acid composition.
Area of Science:
- Hepatology
- Biochemistry
- Pharmacology
Background:
- Cholestasis is characterized by impaired bile flow, leading to hepatic bile acid accumulation and liver injury.
- Alleviating bile acid-induced hepatobiliary toxicity is a key therapeutic objective in cholestasis management.
- Previous research identified glycine-conjugated β-muricholic acid (Gly-βMCA) as a potent anticholestasis agent in Cyp2c70 knockout mice.
Purpose of the Study:
- To investigate the mechanisms and human relevance of Gly-βMCA's therapeutic effects in cholestasis.
- To evaluate the impact of Gly-βMCA on bile acid metabolism and biliary injury in Mdr2 knockout mice, a model with hydrophilic murine bile acid composition.
Main Methods:
- Administration of Gly-βMCA to Mdr2 knockout mice to assess its effects on cholestasis markers.
- Analysis of serum markers (e.g., alkaline phosphatase), liver histology (ductular reaction, cytokine expression), and bile acid profiles.
- Quantification of hepatic and fecal bile acid excretion to determine Gly-βMCA's impact on bile acid pool size and composition.
Main Results:
- Gly-βMCA significantly reduced serum alkaline phosphatase, ductular reaction, and liver cytokine expression in female Mdr2 knockout mice, but showed limited efficacy in males.
- Gly-βMCA decreased hepatic bile acids and the total bile acid pool size in females by promoting fecal excretion, but not in males.
- The presence of endogenous taurine-conjugated muricholic acid (T-MCA) in Mdr2 knockout mice partially limited Gly-βMCA's ability to reduce bile acid hydrophobicity.
Conclusions:
- Gly-βMCA demonstrates therapeutic potential for cholestasis by reducing bile acid pool size and hydrophobicity, particularly in female Mdr2 knockout mice.
- The efficacy of Gly-βMCA is influenced by sex, bile acid hydrophobicity, and endogenous bile acid composition, as seen in the Mdr2 knockout model.
- Gly-βMCA may represent a promising therapeutic strategy for human cholestasis, warranting further investigation into its pharmacokinetics and efficacy across different cholestatic models.
