Targeting CCN2 protects against progressive non-alcoholic steatohepatitis in a preclinical model induced by high-fat feeding and type 2 diabetes

• Published in: Journal of cell communication and signaling 2022-09, Vol.16 (3), p.447-460
• Main Authors: Ren, Jing, Wang, Xiaoyu, Parry, Sarah N., Yee, Christine, Gorrell, Mark D., McLennan, Susan V., Twigg, Stephen M.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; CCN2; Cell Biology; Cell interactions; Collagen; Collagen (type I); Collagen (type III); Connective tissue growth factor; Diabetes; Diabetes mellitus (non-insulin dependent); Fibrosis; High fat diet; Immunoglobulin G; Inflammation; Life Sciences; Monocyte chemoattractant protein 1; mRNA; NAFLD; Neutralizing antibody; Phosphorylation; Proteins; Research Article; Risk factors; Signal transduction; Streptozocin; Type 2 diabetes
• ISSN: 1873-9601; 1873-961X
• DOI: 10.1007/s12079-022-00667-1

Type 2 diabetes is an independent risk factor for non-alcoholic steatohepatitis (NASH) progression and its mediators have not been resolved. In this study, a pathogenic role of cellular communication network factor 2 (CCN2) protein in NASH pathology, was investigated in an established preclinical NASH model. Male wild type C57BL/6 mice received either Chow or high fat diet (HFD) for 26 weeks, with some mice in each group randomly selected to receive low dose streptozotocin (STZ: 3 i.p. injections, 65 mg/kg) at 15 weeks to induce type 2 diabetes. In the final 10 of the 26 weeks mice from each group were administered i.p. either rabbit anti-CCN2 neutralizing antibody (CCN2Ab) or as control normal rabbit IgG, at a dose of 150 µg per mouse twice/week. NASH developed in the HFD plus diabetes (HFD+DM) group. Administration of CCN2Ab significantly downregulated collagen I and collagen III mRNA induction and prevented pro-inflammatory MCP-1 mRNA induction in HFD+DM mice. At the protein level, CCN2Ab significantly attenuated collagen accumulation by PSR stain and collagen I protein induction in HFD+DM. Phosphorylation of the pro-fibrotic ERK signalling pathway in liver in HFD+DM was attenuated by CCN2Ab treatment. Intrahepatic CCN1 mRNA was induced, whereas CCN3 was downregulated at both the mRNA and protein levels in HFD+DM. CCN3 down-regulation was prevented by CCN2Ab treatment. This in vivo study indicates that CCN2 is a molecular target in NASH with high fat diet and diabetes, and that regulation of ERK signalling is implicated in this process.