Z Gastroenterol 2018; 56(08): e249
DOI: 10.1055/s-0038-1668782
Kurzvorträge
Leber und Galle
Leber: Fibrose, Steatose, Speicherkrankheiten – Donnerstag, 13. September 2018, 09:50 – 11:18, 22a
Georg Thieme Verlag KG Stuttgart · New York

Inhibition of TGF-β1 pathway reduces fibrosis in ABCB4ko mouse model

J Werle
1   Medizinische Fakultät Mannheim der Universität Heidelberg, Molekulare Hepatologie, AG Dooley, Mannheim, Deutschland
,
ML Caruso
2   University of Bari Medical School, Department of Biomedical Sciences and Human Oncology, Bari, Italien
,
G Giannelli
2   University of Bari Medical School, Department of Biomedical Sciences and Human Oncology, Bari, Italien
,
S Hammad
1   Medizinische Fakultät Mannheim der Universität Heidelberg, Molekulare Hepatologie, AG Dooley, Mannheim, Deutschland
3   Faculty of Veterinary Medicine, South Valley University, Department of Forensic and Toxicology, Qena, Ägypten
,
S Dooley
1   Medizinische Fakultät Mannheim der Universität Heidelberg, Molekulare Hepatologie, AG Dooley, Mannheim, Deutschland
› Author Affiliations
Further Information

Publication History

Publication Date:
13 August 2018 (online)

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Background and aims:

Since the only therapy of end-stage liver disease still is transplantation, the need for an early treatment in the stage of fibrosis is becoming more important. The transforming growth factor (TGF)-β has been identified as a master regulator of liver fibrogenesis.

Here we targeted the TGF-β1 pathway via a small molecule, Galunisertib, which is inhibiting ALK5 intracellularly and thereby the phosphorylation of SMAD2/3. The inhibitor has already been tested, among others, in clinical trials phase II to treat hepatocellular carcinoma patients (NCT02423343).

Methods:

ABCB4ko mice, a well-established model for CLD, were treated at the age of 6 months. Twice a day the animals received 150 mg/kg body weight Galunisertib via oral gavage. Two days after the last dosage, blood plasma and livers were harvested for standard CLD assessments.

Results:

No changes were observed in body weight of Galunisertib-exposed mice compared to vehicle treated or untreated group. Phosphorylation of SMAD2 showed a significant reduction in the number of positive stained hepatocytes and non-parenchymal cells, as estimated by immunostaining after Galunisertib administration. Analysis of TGF-β1 pathway target genes further indicates the efficacy of the treatment.

Moreover, Galunisertib reduced the level of ECM components as tested by Picro-Sirius Red staining, hydroxyproline analysis and collagen expression on mRNA level. Furthermore anti-fibrotic genes, e.g. MMPs, were upregulated by the treatment.

The downregulated TGF-β1 cascade did not result in less activated hepatic stellate cells but achieved a significant change in ECM constituents, as evident by a decrease in laminin and fibronectin. Interestingly already in this early stage of CLD, fibrosis, the carcinogenic β-catenin pathway was downregulated in the animals treated with Galunisertib.

Conclusion:

Galunisertib shows a trend to regress fibrosis in the ABCB4ko model of CLD. This is not only due to a less fibrogenic phenotype, but also by modulating the biochemical composition of the deposited ECM. The downregulation of β-catenin pathway on the other hand might indicate the stopped progress or even regress of CLD by the treatment with Galunisertib.