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Published on: September 15, 2018
Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study
Laura Guerrero1, Lorena Carmona-Rodríguez1, Fátima Milhano Santos1
1Functional Proteomics Labortory, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
Insights
Progressive familial intrahepatic cholestasis type 3 (PFIC3) involves liver damage due to ABCB4 transporter mutations. This study reveals key molecular changes, offering new insights for PFIC3 disease management.
Area of Science:
- Hepatology
- Molecular Biology
- Genetics
Background:
- Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare, severe pediatric liver disease.
- It stems from mutations in the phosphatidyl choline transporter ABCB4 (MDR3), causing bile acid accumulation and liver damage.
- Current treatments are limited, with liver transplantation being the primary option.
Purpose of the Study:
- To investigate the molecular pathogenesis of PFIC3.
- To identify key cellular processes and molecular players involved in PFIC3 progression.
- To provide a foundation for novel therapeutic strategies.
Main Methods:
- Integrated proteomics and phosphoproteomics analysis of human liver samples.
- Validation of findings in a PFIC3 murine model.
- Differential expression and phosphorylation analysis.
Main Results:
- Identified 6246 protein groups, with 324 differentially expressed in PFIC3.
- Detected 215 differentially phosphorylated phosphopeptides (157 protein groups), including MDR3.
- Highlighted dysregulation of inflammation, metabolic reprogramming, cytoskeleton, extracellular matrix, and cell proliferation.
Conclusions:
- The study provides a comprehensive molecular understanding of PFIC3 pathogenesis.
- Identified molecular pathways offer potential targets for future therapeutic interventions.
- Findings contribute to improved clinical management strategies for PFIC3 patients.
Abstract:
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.
