Non-alcoholic steatohepatitis with fibrosis in diabetes: clinical exploration and targeting CCN family members in a pre-clinical rodent model

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) is a risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and its progression to the severe phenotype of non-alcoholic steatohepatitis (NASH) fibrosis. The profibrotic protein, CCN2 and the antifibrotic protein, CCN1 have been implicated in the development of NASH fibrosis, but their exact roles are currently unknown.

Aims: (1) To evaluate the prevalence of advanced liver fibrosis in individuals attending a dedicated diabetes and liver clinic. (2) To explore the role of CCN2 and CCN1 in the development and progression of NASH fibrosis. (3) To investigate the utility of circulating CCNs as potential blood biomarkers for NASH fibrosis.

Methods: Four studies were conducted. Firstly, a retrospective audit of the CPC RPAH Diabetes and Liver Clinic was performed. Next, two animal studies were performed using a pre-clinical model of NASH fibrosis induced by high fat feeding and diabetes (FaD model) in mice with hepatocyte gene deletion of CCN2 and CCN1. Finally, circulating CCNs were measured in blood samples from humans and mice with diabetes +/- NASH fibrosis.

Results: Advanced liver fibrosis was common in adults with T2DM. Mice with hepatocyte CCN2 deletion developed less liver fibrosis, whilst mice with hepatocyte CCN1 deletion developed more liver fibrosis, when compared with control mice in the FaD model. These histological results by quantitative image analysis as the main study endpoint were supported by concordant changes in mRNA levels of fibrosis markers. Circulating CCNs did not perform well as biomarkers of NASH fibrosis, but this may be due to the relatively small study group size.

Conclusions: The growing burden of disease posed by NASH fibrosis in individuals with T2DM highlights the need for increasing clinical and pre-clinical research into this area. The results of this thesis indicate that CCN2 and CCN1 may be potential therapeutic targets, and further studies in this area are needed.