DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Monoacylglycerol lipase, a new immunometabolic therapeutic target for liver diseases – HEPAMAG

Submission summary

Non-alcoholic fatty liver disease, the hepatic hallmark of the metabolic syndrome, and alcoholic liver disease are leading causes of chronic liver injury that share common pathophysiological features, ranging from steatosis to steatohepatitis, fibrosis and cirrhosis, the latter bearing a grim prognosis;. Efficient pharmacological treatments for fatty liver disease are limited, and there is currently no approved treatment for liver fibrosis. Consequently the concept of reprogramming lipid metabolism in parenchymal and non-parenchymal cells has emerged as a key new concept that may be considered to limit hepatocyte injury and inflammation during fatty liver disease.

Monoacylglycerol lipase (MAGL) is the rate limiting enzyme in the degradation of monoacylglycerols. In addition to its role in lipid metabolism, MAGL is a pivotal component of the endocannabinoid system, as it converts 2-arachydonoyl-glycerol (2-AG), an endogenous ligand for the cannabinoid receptors CB1 and CB2, into arachidonic acid . Recent studies have identified inhibition of MAGL as an interesting anti-inflammatory strategy for inflammatory diseases, by a mechanism that relies on a shift of lipid metabolism in inflammatory cells, from arachidonic acid towards 2-AG.

The French and Austrian partners will combine their leading expertise in liver pathophysiology (French and Austrian teams, endocannabinoid signaling and liver inflammation (French Team), lipid and bile acid metabolism (Austrian Team, to investigate whether MAGL may constitute a novel immunometabolic therapeutic target for fatty liver diseases. Our hypothesis is that deficiency/inhibition of MAGL and its downstream metabolites will reprogram lipid metabolism of specific liver cell types, leading to attenuation of several key mechanisms involved in fatty liver disease progression, in particular inflammation, liver injury and fibrosis. Whether the beneficial consequences of MAGL antagonism are mediated via cannabinoid receptor signaling or other pathways involved in 2-AG metabolism will also be explored.

The project is based on preliminary results of the 2 groups, showing that MAGL inhibition results in anti-inflammatory effects in vivo, associated with acceleration of fibrosis regression. Moreover, pharmacological inhibition of MAGL in liver fibrogenic cells and macrophages results in anti-inflammatory and anti-fibrogenic effects in the liver. Collectively, these findings invite further explorations on the potential benefits of MAGL inhibition in liver inflammation and fibrogenesis.

Our project includes 3 aims involving efficient team-work, and sharing of unique tools, techniques and scientific expertise. In aims 1 and 2, we will combine experiments in animal models and cultured cells to address the hypothesis that liver cell-specific genetic deletion of MAGL and pharmacological MAGL inhibition will protect against immunometabolic alterations induced by fatty liver-induced injury (Aim 1) and fibrosis (Aim 2). In aim 3, we will extrapolate potential findings from mouse models and in vitro studies, to human diseases owing to the access to human liver samples and monocytes from patients suffering from different stages of ALD and NAFLD. The feasibility of this project is high, since the experimental models including mouse models and human cells are currently available or under development, and all technical approaches are perfectly mastered by the two groups.

By identifying the impact of MAGL on the different stages of chronic liver disease progression and characterizing the interplay between specific liver cell types in these processes, we will provide a better understanding of the molecular mechanisms linking lipid metabolism to inflammation and fibrogenesis. Our data are likely to pave the way for the development of new therapeutic strategies for chronic liver disease, by advancing the recently discovered therapeutic potential of MAGL inhibitors to the management of fatty liver diseases

Project coordination


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


MUV Medical University Vienna

Help of the ANR 260,352 euros
Beginning and duration of the scientific project: March 2016 - 36 Months

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