P- 21 docosahexaenoic acid and its derivative maresin1 improve chronic liver damage associated with the promotion of apoptosis pathways and liver regeneration in a sprague-dawley model.

Introduction and Objectives: Liver fibrosis is a complex process characterized by excessive accumulation of extracellular matrix (ECM) associated with chronic injury inflammation and an alteration of liver architecture as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma and liver failure. The ω-3 Docosahexaenoic (DHA) fatty acids and their derivative Maresin-1 (MaR1) have been shown to have pro-resolutive, anti-inflammatory, and hepatoprotective liver effects on acute models of liver study, but their role in apoptosis and liver regeneration remains to be elucidated. This study aimed to analyze the role of DHA+MaR1 in the prevention and restoration of liver fibrosis damage, enhancing a regenerative phenotype in an animal model of chronic liver damage. Materials and Methods: Sprague-Dawley rats were inducing liver fibrosis by injections of diethylnitrosamine (DEN) 50mg/ml twice a week and treated with DHA with or without MaR1 (4ng/g daily) for ten weeks. Biochemical parameters, biopsy analysis, qRT-PCR (RIPK3, Bax, BCL-2 and P53), protein expression of Ki67, pBCL-2 and the apoptotic index by the terminal-deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) was assayed. All data were statistically analyzed by GraphPad Prism v9 software. Results: DHA+MaR1 animals, levels of AST, ALT, and albumin were normalized compared to DEN alone. Inflammation and necrotic areas were reduced by DHA+MaR1 treatment, improving liver cytoarchitecture. Cell proliferation, evaluated as mitotic activity index, was increased in the MaR1 group. Upregulation of Ki67, P53, and Bax was observed in the DHA+MaR1 groups, while the expression of Bcl-2 and RipK3 decreased. Also, the TUNEL assay shows that DHA and DHA+MaR1 promote apoptosis in hepatocytes. Conclusions: Taken together, these results suggest that DHA+MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and apoptosis and restoring the damaged parenchyma. These results open the possibility of DHA + MaR1 as potential therapeutic agents in fibrosis and other liver pathologies. Funding: Fondecyt Iniciación 11200258