Characterization of Novel Targets for Preventing Fibrosis Evolution in Nonalcoholic Fatty Liver Disease (NAFLD)

As a consequence of obesity pandemic, non-alcoholic steatohepatitis (NASH) has become the most prevalent chronic liver disorder worldwide and is a leading cause of liver fibrosis in Western countries. Despite chronic inflammation is seen as the driving force promoting NASH evolution, therapies targeting liver inflammation are still very limited. Therefore, this doctoral project has investigated the capacity of the anti-inflammatory mediator Annexin A1 (AnxA1) and the anti-inflammatory effects of a cholesterol-free ketogenic diet of influencing the experimental NASH progression. The first part of the study revealed as the exogenous administration of human recombinant (hr) AnxA1 improved parenchymal injury, lobular inflammation, and fibrosis in NASH mice. Such an effect depended on the capacity of hrAnxA1 to reduce macrophage aggregation and their production of pro-fibrogenic mediators. Collectively, these results indicate that, besides ameliorating hepatic inflammation, AnxA1 is effective in preventing NASH-associated fibrosis by interfering with macrophage functional features. Given the lack of therapies for NAFLD, lifestyle changes and diet are the only effective interventions. Recently, ketogenic diets (KDs) have been increasingly used for weight loss but their efficacy in improving NASH is still controversial. The second part of the study demonstrated that KD administration improved glucose and lipid metabolism along with insulin resistance. These metabolic effects were associated with an amelioration in gut dysbiosis along with the histological severity of steatosis and necro-inflammation. Mice receiving KD also showed a lowering in hepatic monocyte-derived macrophage infiltration and collagen fibres deposition. Altogether, these results suggest that a cholesterol-free ketogenic diet is effective in improving metabolic derangements and steatohepatitis and it might represent a potential therapeutic strategy for NAFLD.