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Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2 mice

Renxue Wang1, Jonathan A Sheps1, Lin Liu1

  • 1BC Cancer Research Centre, Vancouver, British Columbia, Canada.

Journal of Lipid Research
|November 13, 2018
PubMed

Insights

Highly hydrophilic bile acids, like those in Bsep mice, can prevent liver damage in Mdr2 mice, a model for progressive familial intrahepatic cholestasis type 3. This suggests a potential therapeutic strategy for liver diseases caused by bile acid imbalance.

Area of Science:

  • Hepatology and Gastroenterology
  • Molecular and Genetic Medicine
  • Bile Acid Metabolism

Background:

  • Progressive familial intrahepatic cholestasis types 2 and 3 (PFIC2/PFIC3) are severe liver diseases caused by genetic defects in bile salt export pump (BSEP) and multidrug resistance protein 3 (MDR3), respectively.
  • Mdr2 knockout mice, a model for PFIC3, develop liver pathology including cholangitis, fibrosis, and hepatocellular carcinoma due to toxic, non-micelle-bound bile acids.
  • Bsep knockout mice exhibit altered bile acid profiles with increased hydrophilic bile acids.

Purpose of the Study:

  • To investigate whether the hydrophilic bile acid profile of Bsep knockout mice can protect against liver damage in Mdr2 knockout mice (PFIC3 model).
  • To assess the therapeutic potential of hydrophilic bile acids in mitigating liver pathology associated with MDR3 deficiency.

Main Methods:

  • Generation of double knockout (DKO) mice lacking both Bsep and Mdr2.
  • Analysis of bile acid composition and liver pathology in DKO mice compared to single knockouts.
  • Gene expression profiling of DKO mouse livers.
  • Administration of tetrahydroxylated bile acids (THBAs) to Mdr2 mice to evaluate protective effects.

Main Results:

  • DKO mice exhibited bile acid profiles similar to Bsep mice, characterized by increased hydrophilic muricholic acids and THBAs, and reduced hydrophobic cholic acid.
  • DKO mice were protected from the liver pathology observed in Mdr2 littermates, with suppressed gene expression changes associated with the Mdr2 mutation.
  • Feeding THBAs partially alleviated liver damage in Mdr2 mice, indicating a protective role of hydrophilic bile acids.

Conclusions:

  • Altering biliary bile acid composition towards more hydrophilic forms, including the introduction of THBAs, can prevent progressive liver disease in the Mdr2 (PFIC3) mouse model.
  • This study highlights the potential of modulating bile acid hydrophilicity as a therapeutic strategy for PFIC3 and related liver conditions.
Keywords:
bile acids and salts/biosynthesiscancergene expressionhepatic cellular carcinomahydrophobicityinflammationliver fibrosisprogressive familial intrahepatic cholestasistetrahydroxylated bile acids

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