Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption

Tardelli, Matteo; Bruschi, Francesca Virginia; Claudel, Thierry; Fuchs, Claudia D.; Auer, Nicole; Kunczer, Victoria; Stojaković, Tatjana; Scharnagl, Hubert; Habib, Aı̈da; Grabner, G; Zimmermann, R.; Lotersztajn, Sophie; Trauner, Michael

doi:10.1194/jlr.m093369

Cited by 28 publications

(20 citation statements)

References 38 publications

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“…First, we confirmed the resistance of Mgll −/− mice to high fat diet- (HFD-)induced obesity reported by others [ 28 , 30 , 40 ]. We observed no weight or body composition differences between WT and Mgll −/− mice at 6 weeks of age while the mice were on a standard chow diet ( Figure 1 A,C,D).…”

Section: Resultssupporting

confidence: 88%

“…This family is also suspected of being detrimental to cholesterol metabolism, being positively correlated with non-HDL plasma concentrations and reduced with a dietary intervention that improved cholesterol homeostasis in hamsters [ 51 ]. Interestingly, Mgll −/− mice have reduced cholesterol levels when fed a HFD as compared to controls [ 28 ] (though others have reported only trends in a western diet) [ 40 ], which one could speculate may be related in part to decreased Coriobacteriaceae levels. However, the idea that Coriobacteriaceae may regulate cholesterol metabolism is still controversial, as there is also evidence that improved cholesterol metabolism related to increased biliary cholesterol excretion results in deceases in Coriobacteriaceae as well as Erysipelotrichaceae levels [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

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Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota

Dione

Lacroix

Taschler

et al. 2020

Cells

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Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. Mgll knockout mice (Mgll−/−) exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG’s) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that Mgll−/− mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, Mgll−/− mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. Mgll−/− mice on a chow diet exhibited significantly higher levels of Hydrogenoanaerobacterium, Roseburia, and Ruminococcus than WT mice. The relative abundance of the Lactobacillaceae and Coriobacteriaceae and of the Lactobacillus, Enterorhabdus, Clostridium_XlVa, and Falsiporphyromonas genera was significantly altered by HFD in WT but not Mgll−/− mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of Mgll−/− mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs.

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Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota

Dione

Lacroix

Taschler

et al. 2020

Cells

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“…MGL-KO mice accumulate different MAG species in various tissues and are resistant to diet-induced obesity and protected from the development of liver steatosis [179][180][181]. In addition to its role within the lipolytic cascade, MGL is particularly important in the endocannabinoid system.…”

Section: Mgl and Its Interaction Partnersmentioning

confidence: 99%

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

et al. 2020

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The catabolism of intracellular triacylglycerols (TAGs) involves the activity of cytoplasmic and lysosomal enzymes. Cytoplasmic TAG hydrolysis, commonly termed lipolysis, is catalyzed by the sequential action of three major hydrolases, namely adipose triglyceride lipase, hormone-sensitive lipase, and monoacylglycerol lipase. All three enzymes interact with numerous protein binding partners that modulate their activity, cellular localization, or stability. Deficiencies of these auxiliary proteins can lead to derangements in neutral lipid metabolism and energy homeostasis. In this review, we summarize the composition and the dynamics of the complex lipolytic machinery we like to call “lipolysome”.

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“…Further studies showed that when Mgl -/- animals were challenged with high fat diet feeding, great amounts of 2-AG were detected in the brain, although affecting neither food consumption nor body weight, therefore evidencing cannabinoid receptors desensitizing effects[ 23 ]. Notably, the liver content of certain species of saturated and unsaturated MGs were highly enriched in Mgl -/- , showing after 12 wk high fat diet better insulin sensitivity and glucose tolerance[ 31 , 32 ]; although whether adipose depots or skeletal muscle were the main players in determining this phenotype, was not thoroughly investigated. Several other works evidenced a role of MGL in tumor growth/metabolism as well as oncogenic signaling[ 33 ], being associated with gastrointestinal stromal tumors[ 34 ] and hepatocellular carcinoma (HCC); others instead showed that MGL deletion resulted into significant colorectal cancer growth inhibition[ 35 ] while also reducing ischemia/reperfusion-induced lung injury and inflammation[ 36 , 37 ].…”

Section: Pre-clinical Studies On Monoacylglycerol Lipase Deletion/inhmentioning

confidence: 99%

Monoacylglycerol lipase reprograms lipid precursors signaling in liver disease

Tardelli¹

2020

WJG

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Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which eventually progress to cirrhosis and hepatocellular carcinoma. Monoacylglycerol lipase is the last enzymatic step in the hydrolysis of triglycerides, generating glycerol and fatty acids (FAs), which are signaling precursors in physiology and disease. Notably, monoacylglycerol lipase (MGL) also hydrolyzes 2-arachidonoylglycerol, which is a potent ligand within the endocannabinoid system, into arachidonic acid - a precursor for prostaglandin synthesis; thus representing a pivotal substrates provider in multiple organs for several intersecting biological pathways ranging from FA metabolism to inflammation, pain and appetite. MGL inhibition has been shown protective in limiting several liver diseases as FAs may drive hepatocyte injury, fibrogenesis and de- activate immune cells, however the complexity of MGL network system still needs further and deeper understanding. The present review will focus on MGL function and FA partitioning in the horizons of liver disease.

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Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption

Abstract: Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption.

Cited by 28 publications

References 38 publications

Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota

Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota

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

Monoacylglycerol lipase reprograms lipid precursors signaling in liver disease

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