Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism

Abstract

Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study, we used a biochemical screen in Saccharomyces cerevisiae to identify and characterize putative hydrolases involved in FAEE catabolism. We found that Yju3p, the functional orthologue of mammalian monoacylglycerol lipase (MGL), contributes >90% of cellular FAEE hydrolase activity, and its loss leads to the accumulation of FAEE. Heterologous expression of mammalian MGL in yju3Δ mutants restored cellular FAEE hydrolase activity and FAEE catabolism. Moreover, overexpression or pharmacological inhibition of MGL in mouse AML-12 hepatocytes decreased or increased FAEE levels, respectively. FAEEs were transiently incorporated into lipid droplets (LDs) and both Yju3p and MGL co-localized with these organelles. We conclude that the storage of FAEE in inert LDs and their mobilization by LD-resident FAEE hydrolases facilitate a controlled metabolism of these potentially toxic lipid metabolites.

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

“…Recent data suggest that MGL also degrades prostaglandin glycerol esters, which represent still poorly characterized inflammatory mediators (Savinainen et al, 2014). Finally, MGL has been implicated in non-oxidative ethanol metabolism by hydrolyzing fatty acid ethyl esters which are produced in the body in response to alcohol consumption (Heier et al, 2016).…”

Nonoxidative ethanol metabolism in humans—from biomarkers to bioactive lipids

“…Interestingly, MGL as well as FAEE were found to associate with lipid droplets (LDs), which are cellular storage organelles of hydrophobic esters such as triacylglycerol or steryl esters. This suggests that FAEE are transiently stored in LDs and hydrolyzed by LD‐associated MGL .…”

“…FAEEH activities have been measured in a multitude of tissues, and highest activities have been observed in pancreas and liver . Several serine hydrolases with FAEEH activity have been identified including hepatic carboxylesterase isoforms, hormone‐sensitive lipase and monoacylglycerol lipase (MGL) . Based on the abundance of carboxylesterase isoforms Diczfalusy et al concluded that Es‐4 (also known as Ces1f) may be responsible for a considerable portion of rat hepatic FAEEH activity.…”

The Lipolysome—A Highly Complex and Dynamic Protein Network Orchestrating Cytoplasmic Triacylglycerol Degradation

“…MGL is ubiquitously expressed among tissues, with slightly different molecular sizes [175]. The enzyme exhibits high hydrolytic activity against MAGs [176]; however, it was also shown to hydrolyze prostaglandin glycerol esters [177] and FA ethyl esters [178].…”