The monoacylglycerol pathway is important mainly in rebuilding TAG from absorbed dietary fat

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The main function of the monoacylglycerol pathway (Fig. 3.6) is to resynthesize TAG from the monoacylglycerols formed during the digestion of fats in the small intestine. Therefore, this mechanism is one by which existing TAG are modified rather than one by which new fat is formed (Section 5.1.3). During the hydrolysis of dietary TAG in the intestinal lumen by pancreatic lipase, the fatty acids in positions 1 and 3 are preferentially removed. The remaining 2-monoacylglycerols are relatively resistant to further hydrolysis. When 2-mono-acylglycerols, radiolabelled in both fatty acid and glycerol moieties, were given in the diet, the molecules were absorbed intact, reacylated and secreted into the lymph without dissociation of the label. The pathway involves a stepwise acylation first of monoacylglycerols, then diacylglycerols and was first discovered by Georg Hubscher's research team in Birmingham, UK in 1960.

The reactions are catalysed by enzymes in the endoplasmic reticulum of the enterocytes of many species of animals. There is some controversy about the exact location of the enzymes and this is described in some detail in the review by Lehner and Kuksis (see Further Reading). The 2-mono-acylglycerols are the preferred substrates compared with 1-monoacylglycerols and the rate of the first esterification is influenced by the nature of the fatty acid esterified at position 2. Monoacylglycerols with medium-chain saturated or longer chain unsaturated fatty acids are the best substrates. However, it is worth stressing, as we do so frequently in this book, that such generalizations are made almost entirely from the results of studies with subcellular preparations in vitro, which may not necessarily obtain in vivo. Differences in solubility of the added substrates may limit the proper interpretation of the results. If the reaction of monoacylglycerol acyltransferase were completely stereospecific, it would be expected that the reaction products would be entirely either sn-1,2- or sn-2,3-diacylglycerols. In fact, several studies, employing different analytical methods, have indicated that the reaction mixture contains about 90% 1,2- and about 10% 2,3-diacylglycerols, so the reaction may not be completely stereospecific.

Diacylglycerol acyltransferase is specific for 1,2-sn-diacylglycerols and will not acylate the sn-2,3- or sn-1,3-isomers. Diunsaturated or mixed-acid dia-cylglycerols are better substrates than disaturated compounds. Again, we have to be cautious when we interpret results of this kind. Lipids containing unsaturated fatty acids are more easily emulsified than saturated ones, so that we may not be observing differences in specificity of the enzyme for fatty acid composition, but differences in solubility of the substrates when the enzyme assays are performed in vitro. There is little information on whether diacylglycerol acylating activity in the monoacylglycerol pathway is identical to that in the glycerol phosphate pathway or whether different isoforms of the enzyme are involved.

Attempts to purify the individual enzymes involved in the monoacylglycerol pathway have met with only partial success. Frequently (but not always!) the partly purified preparation has contained all three enzyme activities: mono-acylglycerol and diacylglycerol acyltransferases and acyl-CoA synthetase. This has led to the concept that there is a complex of enzymes acting in concert, now generally referred to as 'triacylgly-cerol synthase' or 'triacylglycerol synthase complex'. A molecular mass of 350 kDa has been proposed by the Canadian, Kuksis. A more purified preparation that migrated as a 37 kDa band on SDS-

PAGE had monoacylglycerol acyltransferase activity, but whether it was a genuine subunit of the complex or a proteolytic fragment was not clear.

The monoacylglycerol pathway has also been demonstrated in the liver and adipose tissue of the hamster and the rat and these enzymes have also been partly purified. The activity is particularly high in pig liver. Under certain conditions it appears to compete with the glycerol phosphate pathway for acyl groups and may serve to regulate the activity of the latter pathway. The origin of the monoacylglycerol substrate in tissues other than intestine is not known and the role of the pathway in these other tissues is far from clear.

The liver and intestinal enzymes differ in substrate specificity, thermolability and response to different inhibitors, suggesting the existence of separate isoforms. Because the liver isoform has a preference for 2-monoacylglycerols that contain polyunsaturated fatty acids, it has been suggested that one of its roles may be to prevent excessive degradation of polyunsaturates under conditions of high rates of P-oxidation. Consistent with this proposal is the high activity of liver mono-acylglycerol acyltransferase in neonatal life and in hibernating animals. The adipose tissue isoform is particularly active in birds during migration. The normal neonatal rise in monoacylglycerol acyl-transferase is attenuated in rat pups given an artificial high-carbohydrate diet compared with those sucking mother's milk.

An alternative route to TAG assembly in intestinal tissue was discovered by Lehner and Kuksis in the early 1990s. This involves the transfer of acyl groups between two diacylglycerol molecules without the intervention of acyl-CoA, catalysed by diacylglycerol transacylase (Fig. 3.6). The activity is located in endoplasmic reticulum and has been solubilized and purified to homogeneity as a 52 kDa protein. Its precise function is unknown but because its activity can be as much as 15% of that of diacylglycerol acyltransferase, it could supply significant amounts of TAG. The substrates are 1,2-and 1,3-diacylglycerols and the monoacylglycerol product can also be fed into the monoacylglycerol pathway.

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  • Maria
    What is monoacyl glycerol pathway?
    2 years ago

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