Involvement of monoacylglycerol lipase (MAGL) in non alcoholic steatohepatitis (NASH) evolution – IMAGINE

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and a prominent cause of chronic liver injury. NASH is a leading health-care concern, has the potential for cirrhosis, and ultimately organ dysfunction and death. Despite its prevalence and severity, there is no approved therapy for NASH and its complications. The identification of specific targets that could disrupt the sequence of events underlying NAFLD progression and treat its complications is of utmost importance.
Changes in lipid metabolism not only drive hepatocyte injury but also control immune cell phenotype and fibrogenic cell activation. Therefore, reprogramming lipid metabolism in hepatocytes and immune cells has recently emerged as a novel therapeutic approach for NAFLD. Monoacylglycerol lipase (MAGL) catalyzes the final step of triglyceride degradation and displays pro-inflammatory properties.
Recent data obtained by the consortium highlight that MAGL is at the cross-road between liver metabolic dysfunction and inflammation. These data invite to further explore how MAGL impacts on lipid metabolism and the potential benefits of MAGL inhibition, either pharmacologically or by modifying diet composition, on NAFLD progression. The three teams will combine their expertise in NASH, liver inflammation and lipid metabolism to determine whether and how MAGL may constitute a novel therapeutic target for the treatment of NAFLD. Our hypothesis is that inhibition of MAGL and its downstream targets will reprogram lipid metabolism of immune and/or liver epithelial cells, leading to attenuation of key steps underlying NAFLD progression.
IMAGINE includes four aims involving efficient teamwork and sharing of unique tools, techniques and scientific expertise between the three groups. We will combine experiments in cell-specific MAGL invalidated animal models and cultured cells to study the impact of lipid reprograming by MAGL in hepatocytes, myeloid and T lymphocytes on NAFLD progression (Task1). In Task 2, in vitro studies will address how exogenous metabolic signals regulate MAGL expression in hepatocytes and immune cells, and the consequences on their intracellular metabolism. In Task 3, we will elucidate how modifying the composition of the diet may limit NAFLD progression by reprogramming lipid metabolism changes in hepatocytes and/or immune cells promoted by MAGL. Task 4 will be devoted to extrapolation of our findings in human samples using liver samples and PBMC from patients at various stages of NAFLD/NASH.
Data obtained will pave the way for the design of novel therapies targeting MAGL in the context of NAFLD.