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Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis

J F Deleuze1, E Jacquemin, C Dubuisson

  • 1Unité INSERM U 347, le Kremlin Bicêtre, France.

Hepatology (Baltimore, Md.)
|April 1, 1996
PubMed

Insights

Progressive familial intrahepatic cholestasis (PFIC) may result from a lack of MDR3 P-glycoprotein, which impairs biliary phospholipid secretion. This mirrors a murine model, suggesting bile acid toxicity in the absence of phospholipids.

Area of Science:

  • Hepatology and Genetics
  • Molecular Biology and Biochemistry

Background:

  • The murine mdr2 gene encodes a phosphatidylcholine flippase, crucial for biliary phospholipid secretion.
  • Disruption of mdr2 in mice causes a hepatic disorder characterized by impaired bile formation.

Observation:

  • A subtype of human progressive familial intrahepatic cholestasis (PFIC) with high gamma-glutamyltranspeptidase (GGT) exhibits similarities to mdr2-deficient mice.
  • Absence of MDR3 (human mdr2 homolog) mRNA and decreased biliary phospholipid levels were noted in PFIC patients.

Findings:

  • The absence of functional MDR3 P-glycoprotein is implicated as a cause of this PFIC subtype.
  • This deficiency leads to a loss of biliary phospholipid secretion, similar to the mdr2-/- murine model.

Implications:

  • The findings suggest that MDR3 deficiency may render the biliary epithelium susceptible to bile acid toxicity.
  • Understanding this mechanism could inform therapeutic strategies for PFIC and related cholestatic disorders.

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