Related Experiment Video
Updated: Aug 15, 2026
Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and
Yury Popov1, Eleonora Patsenker, Peter Fickert
1Laboratory of Liver Research, Department of Medicine I, University of Erlangen-Nuremberg, Germany; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Background/Aims:
Mdr2 (Abcb4)-/- mice develop hepatic lesions resembling primary sclerosing cholangitis. Our aim was to characterize the evolution of fibrosis in Mdr2-/- mice.
Methods:
Mdr2-/-mice and their wild-type littermates were sacrificed at 2, 4 and 8 weeks after birth. Hepatic collagen was determined biochemically. Fibrosis related transcript levels were quantified from livers by real-time RT-PCR, and MMP activities determined by substrate assays. Liver histology was assessed by connective tissue staining and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA).
Results:
Mdr2-/- mice demonstrated a time-dependent increase of relative and total hepatic collagen (fivefold at 8 weeks, compared to wildtype controls), and maximal alpha-SMA immunoreactivity at 4 weeks. Compared to wildtype controls profibrogenic mRNA levels for procollagen alpha1(I), TGFbeta1, TGFbeta2, MMP-2 and -13, TIMP-1, PDGFbeta receptor, and PAI-1 were upregulated up to 27-fold. Most transcripts peaked at 4 weeks, but procollagen alpha1(I) mRNA increased steadily, TIMP-1 mRNA was constantly elevated (20-fold), MMP-13 mRNA was suppressed and interstitial collagenase and gelatinase activities were downregulated.
Conclusions:
Mdr2-/- mice spontaneously progress to severe biliary fibrosis. This is due to a characteristic temporal pattern of upregulated profibrogenic and downregulated fibrolytic genes and activities. These mice are an attractive model to test potential antifibrotics for the treatment of (biliary) liver fibrosis.
Insights
Mdr2-/- mice spontaneously develop severe biliary fibrosis due to altered gene expression. This mouse model is valuable for testing antifibrotic therapies for liver fibrosis.
Area of Science:
- Hepatology
- Fibrosis Research
- Animal Models
Background:
- Mdr2 (Abcb4)-/- mice exhibit hepatic lesions similar to primary sclerosing cholangitis.
- Understanding the progression of liver fibrosis in this model is crucial.
Purpose of the Study:
- To characterize the temporal evolution of hepatic fibrosis in Mdr2-/- mice.
- To identify key molecular changes associated with fibrosis development.
Main Methods:
- Mice were analyzed at 2, 4, and 8 weeks post-birth.
- Assessed hepatic collagen, fibrosis-related gene expression (RT-PCR), MMP activity, and alpha-SMA immunohistochemistry.
Main Results:
- Mdr2-/- mice showed a fivefold increase in hepatic collagen by 8 weeks.
- Profibrogenic genes (e.g., procollagen alpha1(I), TGF-beta) were upregulated up to 27-fold.
- Fibrolytic gene and enzyme activities (e.g., MMP-13) were downregulated.
Conclusions:
- Mdr2-/- mice spontaneously develop severe biliary fibrosis with a distinct temporal gene expression pattern.
- These mice serve as a relevant model for evaluating antifibrotic drugs.
- The study highlights a dysregulation of profibrogenic and fibrolytic pathways in liver fibrosis progression.
