Abstract
New therapeutic concepts developed in rodent models should ideally be evaluated in large animal models prior to human clinical application. COMMD1-deficiency in dogs leads to hepatic copper accumulation and chronic hepatitis representing a Wilson’s disease like phenotype. Detailed understanding of the pathogenesis and time course of this animal model is required to test its feasibility as a large animal model for chronic hepatitis. In addition to mouse models, true longitudinal studies are possible due to the size of these dogs permitting detailed analysis of the sequence of events from initial insult to final cirrhosis. Therefore, liver biopsies were taken each half year from five new born COMMD1-deficient dogs over a period of 42 months. Biopsies were used for H&E, reticulin, and rubeanic acid (copper) staining. Immunohistochemistry was performed on hepatic stellate cell (HSC) activation marker (alpha-smooth muscle actin, α-SMA), proliferation (Ki67), apoptosis (caspase-3), and bile duct and liver progenitor cell (LPC) markers keratin (K) 19 and 7. Quantitative RT-PCR and Western Blots were performed on gene products involved in the regenerative and fibrotic pathways. Maximum copper accumulation was reached at 12 months of age, which coincided with the first signs of hepatitis. HSCs were activated (α-SMA) from 18 months onwards, with increasing reticulin deposition and hepatocytic proliferation in later stages. Hepatitis and caspase-3 activity (first noticed at 18 months) increased over time. Both HGF and TGF-β1 gene expression peaked at 24 months, and thereafter decreased gradually. Both STAT3 and c-MET showed an increased time-dependent activation. Smad2/3 phosphorylation, indicative for fibrogenesis, was present at all time-points. COMMD1-deficient dogs develop chronic liver disease and cirrhosis comparable to human chronic hepatitis, although at much higher pace. Therefore they represent a genetically-defined large animal model to test clinical applicability of new therapeutics developed in rodent models.
Highlights
Chronic hepatic injury activates a general aetiology-independent process characterized by liver regeneration and fibrogenesis
We evaluated COMMD1-deficient dogs as a possible large animal model for chronic hepatitis, in a 42 month lasting longitudinal study
Free copper is highly toxic due to its ability to generate hydroxyl radicals and it has been demonstrated that hepatocellular apoptosis is triggered by copper-induced cell damage [24,25,26]
Summary
Chronic hepatic injury activates a general aetiology-independent process characterized by liver regeneration and fibrogenesis. The absence of the COMMD1 protein in BT, due to a deletion of exon-2 of the COMMD1 gene, results in a progressive accumulation of copper in hepatocytes leading to chronic hepatitis and cirrhosis [16,17] This canine disease was discussed as a potential model for human Wilson’s disease (WD), an autosomal recessive inherited copper storage disorder due to a reduced or absent ATP7B gene expression [18,19,20,21]. These dogs could serve as model for Wilson’s disease and in general for chronic liver disease leading to end-stage liver cirrhosis Because of their size and life-span, the availability of molecular tools, the possibility and easiness to approach the liver with comparable procedures as performed in man, e.g. to take multiple and sequential liver biopsies, combined with a known genetic aetiology these dogs are potentially wellsuited for evaluation of new protocols aimed at enhancing liver regeneration and reduction of fibrosis/cirrhosis. We provide a detailed longitudinal analysis of clinical, clinicopathological, and molecular aspects focusing on regenerative and fibrotic pathways of COMMD1-deficient dogs
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