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Inhibition of monoacylglycerol lipase for the treatment of liver disease: tempting but still playing with fire
  1. Claus Hellerbrand1,2
  1. 1Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
  2. 2Comprehensive Cancer Center (CCC) Erlangen-EMN, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
  1. Correspondence to Professor Claus Hellerbrand, Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen D-91054, Germany; claus.hellerbrand{at}fau.de

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Lipolytic enzymes have received huge attention due to their crucial role in lipid metabolism and as potential pharmacological targets against obesity and its related disorders. Non-alcoholic fatty liver disease (NAFLD) is highly associated with obesity and today, NAFLD is considered to be the most common chronic liver disorders worldwide.1 The NAFLD pathology covers a wide spectrum of changes, ranging from simple steatosis to non-alcoholic steatohepatitis, progressive fibrosis/cirrhosis and hepatocellular carcinoma (HCC). The underlying mechanisms, particularly those that drive disease progression, are only incompletely understood.1 Central drivers appear to be quantitative and qualitative alterations in lipid metabolic pathways in hepatocytes.1 2 In addition, the impact of altered lipid metabolism in non-parenchymal liver cells and immune cells is increasingly recognised.1 3 Importantly, lipids are stored within the cells and act as signalling molecules or precursors thereof, which further enhances the level of complexity how alterations in the lipid metabolism affect the course of obesity-related diseases.

In this regard, monoacylglycerol lipase (MAGL) plays a particularly critical role.4 In the 70th of the last century, MAGL was originally purified from adipose tissue, where it was found to be most abundant besides the brain and the liver.4 Traditionally, MAGL functions as a key lipolytic enzyme in the mobilisation of lipid stores for energy supply or lipid synthesis. MAGL is the rate-limiting enzyme in the hydrolysis of monoacylglyerides (MG) into glycerol and fatty acids. MGs are intermediary lipids deriving from the degradation of phospholipids and neutral lipids. In addition to its role in MG metabolisms, MAGL is a critical component of the endocannabinoid system, as it is catalysing the hydrolysis of 2-arachidonoyl glycerol (2-AG), the most abundant endogenous agonist of cannabinoid receptors in the body. Furthermore, 2-AG is an important source for arachidonic …

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