Monoacylglycerols

1.   Monoacylglycerols - as Components of Oils and Fats

Monoacylglycerols (or "monoglycerides") are esters of the trihydric alcohol glycerol in which only one of the hydroxyl groups is esterified with a long-chain fatty acid, and they can exist in three stereochemical forms.

Formulae for monoacylglycerols

Normally the 1-/3-isomers are not distinguished from each other and are termed 'α-monoacylglycerols', while the 2-isomers are β-monoacylglycerols. They tend to be minor components only of most plant and animal tissues, and indeed would not be expected to accumulate because their strong detergent properties would have a disruptive effect on membranes.

2-Monoacylglycerols are a major end product of the intestinal digestion of dietary fats in animals by the enzyme pancreatic lipase. They are taken up directly by the intestinal cells and converted to triacylglycerols via the monoacylglycerol pathway before being transported in lymph to the liver (see our web pages on triacylglycerols for further details). In addition, it is now recognized that 2-monoacylglycerols and 2-oleoylglycerol in particular have a signalling function in the intestines by activating a specific G-protein-coupled receptor GPR119, sometimes termed the ‘fat sensor’. When stimulated, this causes a reduction in food intake and body weight gain in rats and regulates glucose-stimulated insulin secretion. Oleoylethanolamide and 1-oleoyl-lysophosphatidylcholine act in the same manner, but 2-oleoylglycerol is the most abundant of the potential agonists.

Monoacylglycerols are catabolized in animal cells by the action of a monoacylglycerol lipase with formation of free fatty acids and glycerol. This enzyme is currently of considerable biological interest as it is highly expressed in aggressive human cancer cells and primary tumours. It appears that the resulting high lipolytic activity controls free fatty acid levels in cancer cells, and these feed into a diverse network of pro-tumourigenic signalling lipids, which promote migration, survival and tumour growth in vivo supporting malignancy.

Monoacylglycerols undergo acyl migration very rapidly indeed to form a mixture that contains more than 80% of the 1-/3-form. They can be stabilized and purified by chromatography on adsorbents impregnated with boric acid, provided that great care is taken. It is more usual to analyse them as a 'total' monoacylglycerol fraction isolated by TLC by gas chromatography of the methyl ester derivatives of the fatty acid components.

From a technological standpoint, synthetic monoacylglycerols are important as constituents of commercial detergents. Monoolein has become one of the most important lipids in the fields of drug delivery, emulsion stabilization and protein crystallization.

 

2.  2-Arachidonoylglycerol

2-Arachidonoylglycerol is mainly a product of phosphatidylinositol catabolism, and is important in animal tissues as an endogenous ligand for cannabinoid receptors, i.e. it is an endocannabinoid (like anandamide). It was first detected in brain, where it occurs at levels of nmol/g tissue, but it is now known to be present in many other organs. As a neutral lipophilic molecule, it is possible that 2-arachidonoylglycerol can diffuse freely through membranes to reach the sites of activity, since no active transport system has been identified to date. It is important as a biologically active lipid in its own right but also as a precursor of other bioactive lipids.

Formula for 2-arachidonoylglycerol

As with anandamide, 2-arachidonoylglycerol is synthesised upon demand from phospholipid precursors in cell membranes, probably in raft microdomains, in response to a rise in intracellular calcium levels. Biosynthesis can occur by two routes. Diacylglycerols generated from phosphatidylinositol by the action of phospholipase C are hydrolysed by a calcium-dependent sn-1 specific diacylglycerol lipase to yield 2-arachidonoylglycerol. Phosphatidylinositol 4,5-bisphosphate is the primary precursor in neurons. In an alternative but less likely pathway, a specific phospholipase A1 may act upon phosphatidylcholine to generate 2-arachidonoyl-lysophosphatidylcholine, which is in turn acted upon by a lysophospholipase C to produce 2-arachidonoylglycerol.

Biosynthesis of 2-arachidonoylglycerol

Our web pages on anandamide discuss the general topic of the endogenous cannabinoids, although there is evidence to suggest that 2-arachidonoylglycerol is the more important natural ligand for both the CB1 and the CB2 cannabinoid receptors, key membrane-bound G-proteins. While anandamide may only act as a partial agonist at these cannabinoid receptors, 2-arachidonoylglycerol usually acts as a full agonist. While the two molecules may interact to regulate some processes, the latter has many activities distinct from those of anandamide.

For example, amongst innumerable metabolic functions that have been reported, 2-arachidonoylglycerol is believed to be a messenger molecule that regulates the transmission of signals across synapses, and it is involved as a mediator of inflammatory reactions and immune responses. Thus, immune cells such as platelets and macrophages produce this lipid in response to injury, and this production is thought to be a beneficial response aimed at decreasing proinflammatory mediators. In the brain and the central nervous system, the 2-arachidonoyl-glycerol ‘signalosome' at excitatory synapses consists of a supra-molecular complex in a single functional unit containing three key players in 2-arachidonoyl-glycerol production: phospholipase Cβ, with an activator protein designated mGluR5, and DAGLα. 2-Arachidonoylglycerol is believed to suppress the elevation of cyclooxygenase(COX)-2 expression in response to proinflammotry stimuli and may ameliorateneurodegenerative diseases.

 Recent findings that it has a role in the regulation of the proliferation and invasion of certain types of cancer cells, that it regulates systemic energy metabolism, and that it may be relevant to cardiovascular disease will no doubt stimulate much more interest. It also appears to be important in human reproduction.

2-Arachidonoylglycerol can also function as a precursor of glycerol-linked prostanoids, through a specific and efficient interaction with the enzyme COX-2, but not COX-1, followed by further downstream processing. Thus, prostaglandin H2 glycerol ester is formed first, and this is converted sequentially to esterified forms of PGD2, PGE2, PGF and PGI2 by additional enzymes. These constitute a new class of lipid mediator with distinctive biological properties in their own right. Similarly, oxygenated metabolites are produced by the action of two lipoxygenases and A cytochrome P450 enzyme. For example, the latter enzyme produces two metabolites of 2 arachidonoyl-glycerol, i.e. 2-(11,12-epoxyeicosatrienoyl)-glycerol and 2-(14,15-epoxyeicosatrienoyl)-glycerol, in various animal tissues. Although they do not interact with the prostaglandin receptors, glycerol-linked prostanoids activate both cannabinoid receptors CB1 and CB2 with high affinity and elicit biological responses in cultured cells. Together with analogous lipoxygenase metabolites, they are new members of the endocannabinoid family. Although they are present in tissues at much lower levels than the free acid forms, some of the glycerol-linked prostanoids have much greater biological activity.

The 2-glycerol ether analogue (termed ‘noladin ether’) has similar biological activity in vitro, and it has been reported to occur naturally, but at very low levels, in pig brain.

Catabolism. When isomerized to the 1/3-isomer, 2-arachidonoylglycerol loses its biological potency, and this probably occurs fairly rapidly in vivo. Within cells, it has a short half-life and is rapidly hydrolysed to arachidonic acid and glycerol by the cytosolic monoacylglycerol lipase, but also by two α/β hydrolases, which in consequence have important regulatory functions for many signalling pathways. Inhibitors of the enzyme appear to have pharmaceutical potential as anticancer and anti-inflammatory agents. In brain and probably in other tissues, the arachidonic acid released in this way is recycled into phospholipids, though some may serve as a precursor for pro-inflammatory prostaglandins.

 

References

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Updated May 15, 2014

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