Monoacylglycerol, a new immunometabolic therapeutic target for chronic liver diseases

Alcohol abuse, non-alcoholic fatty liver disease (NAFLD) and cholestatic syndromes are prominent causes of chronic liver injury. These conditions result in hepatocyte or biliary injury, inflammation, fibrosis and cirrhosis. Efficient pharmacological treatments for these conditions are lacking, and no approved treatment for liver fibrosis exists. Monoacylglycerol lipase (MAGL) is the rate limiting enzyme in the degradation of monoacylglycerols, which are short lived intermediates of lipid catabolism derived from extracellular and intracellular sources. In addition to its role in lipid metabolism, MAGL is a pivotal component of the endocannabinoid system, since this enzyme metabolizes 2-arachydonoyl-glycerol (2-AG), an endogenous cannabinoid receptor ligand. The French partner (S Lotersztajn) has demonstrated the role of cannabinoid receptors in the pathogenesis of chronic liver diseases. However, therapeutic development of CB1 antagonists has been put to a hold and clinical development of CB2 agonists is still awaited. In this context, amplifying the actions of endocannabinoids by inhibiting their enzymatic degradation has emerged as an alternative strategy to exploit the endocannabinoid system for possible clinical benefits. The Austrian partner (M Trauner) has a recognized expertise in bile acid and lipid metabolism and has demonstrated the key role of metabolic lipases in determining nuclear receptor signaling and regulation of hepatic function in cholestatic and metabolic liver diseases. The two partners will combine their complementary expertise to investigate whether MAGL may constitute a novel immunometabolic therapeutic target for chronic liver diseases. Our hypothesis is that deficiency/inhibition of MAGL and concurrent accumulation of 2-AG in specific liver cell types will attenuate several key mechanisms in the pathogenesis of alcoholic and non- alcoholic fatty liver disease, in particular liver fibrosis and cirrhosis. The project is based on preliminary results from both groups, showing that MAGL inhibition and CB2 stimulation via increases in 2-AG results in anti-fibrogenic and anti-inflammatory effects in vitro. Our strategy includes 3 tasks that aim to determine whether MAGL invalidation, using pharmacological or genetic approaches (i.e global (available) or cell specific (Task 1) mitigates immunometabolic liver injury (Task 2) ii) and fibrogenesis in the liver. In Task 3, we will validate our key findings in human liver samples and monocytes from patients at different stages of (N)AFLD and alchoholic liver disease. (ALD). The feasibility of our project is high, since it will benefit from available or current development of unique complementary tools and approaches that will be shared among the two partners. We believe that our coordinated work will facilitate a unique understanding of the molecular mechanisms linking lipid metabolism to inflammation and fibrogenesis. Our data should pave the way for the development of novel therapies for fatty liver disease, as well as liver fibrosis and cirrhosis, based on the use of MAGL inhibitors.

Monoacylglycerol lipase (MAGL) is a key enzyme in lipid metabolism and is involved in the final steps of lipid degradation in the body, but little is known in liver disease. Cholestatic liver diseases are characterized by an impairment in bile production due to reduced bile secretion by liver cells or to obstruction of bile ducts, which normally deliver bile from the liver to the intestine to facilite digestion and absorption of fat. Non-alcoholic fatty liver disease (NAFLD) is a very common disorder (affecting 30% of the total population) that refers to a group of conditions with accumulation of fat in the liver of people who drink no significant amounts of alcohol and which can lead to inflammation, fibrosis as well as cirrhosis and cancer of the liver. Since these two liver disorders lack effective pharmacological therapy, it is of major interest to obtain better insights in the disease mechanisms allowing the development of new treatment strategies. In this work we investigated the contribution of MAGL for liver injury in cholestasis and NAFLD and whether its inhibition could ameliorate liver disease. For this purpose we induced cholestasis in MAGL knockout mice and evaluated the effects of pharmacological MAGL inhibition in a mouse model of sclerosing cholangitis (Mdr2 knockout mice). We discovered that mice with absence or inhibition of MAGL were protected against cholestasis and showed reduced liver fibrosis and inflammation. To study the role of MAGL in NAFLD, we fed mice lacking MAGL a high fat diet for 12 weeks and discovered that absence of MAGL also protected these mice against diet-induced NAFLD. Altogether, the molecular and biochemical characterization of our pre-clinical mouse models provided novel mechanistic insights into the pathomechanisms of cholestatic liver disease and NAFLD, allowing the identification of MAGL inhibition as a promising novel treatment strategy for these disorders.