Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling

Abstract

Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL.

Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

“…These data suggest that inhibition of MAGL may limit the production of proinflammatory prostaglandins in the setting of inflammatory disorders 22 32. MAGL inhibitors reduce inflammation and colon alterations in a model of colitis,33 reduce macrophage content and improve atherosclerotic plaque alterations,34 attenuate neuroinflammation in astrocytes22 and display anti-inflammatory and protective effects during acute lung or muscle injury 35 36. Surprisingly, very little is known about the role of MAGL in the liver.…”

Inhibition of monoacylglycerol lipase for the treatment of liver disease: tempting but still playing with fire

“…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.…”

“…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.…”

“…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 acid, the precursor of prostaglandins and other (pro)inflammatory mediators 4. Herewith, MAGL is a central metabolic hub coupling the endocannabinoid and eicosanoid systems.…”

“…Thus, central effects of targeting MAGL need to be carefully assessed, since chronic inactivation of MAGL leads to a 2-AG overload in brain and consecutive desensitisation of brain CB1R receptor signalling 4. Central CB1R inactivation has been related with a higher incidence of depression and other psychiatric side effects, which had led to the withdrawal of the antiobesity drug rimonabant, an inverse CB1R agonist 5.…”