Lecithimcholesterol acyltransferase

HDL is synthesized and secreted from both liver and intestine (Figure 25—5). However, apo C and apo E are synthesized in the liver and transferred from fiver HDL to intestinal HDL when the latter enters the plasma. A major function of HDL is to act as a repository for the apo C and apo E required in the metabohsm of chylomicrons and VLDL. Nascent HDL consists of discoid phosphohpid bilayers containing apo A and free cholesterol. These hpoproteins are similar to the particles found in the plasma of patients with a deficiency of the plasma enzyme lecithimcholesterol acyltransferase (LCAT) and in the plasma of patients with obstructive jaundice. LCAT—and the LCAT activator apo A-I— bind to the disk, and the surface phosphohpid and free cholesterol are converted into cholesteryl esters and... 

Familial lecithimcholesterol acyltransferase (LCAT) deficiency Absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol. Plasma concentrations of cholesteryl esters and lysolecithin are low. Present is an abnormal LDL fraction, lipoprotein X, found also in patients with cholestasis. VLDL is abnormal ( 3-VLDL). 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

It had been known for some years that there is more than one form of apoA-I in plasma (El, L23, 07), when Nestruck et al. (N5) reported that four forms of apoA-I could be isolated by preparative flat bed isoelectric focusing. The two major forms in human plasma (referred to as apoA-Ij and apoA-I2 by Nestruck et al., but as isoforms or isoproteins 4 and 5 in this review (following references S9, Zl, and Z6), focus at pi 5.62 and 5.53, respectively, and contain 71 and 19%, respectively, of total apoA-I. All forms had an identical apparent Mr and common antigenicity to antisera against apoA-I. The amino acid analyses of isoforms 4, 5, and 6 resembled previously published apoA-I analyses (Bl, B43) and these isoforms activated purified lecithimcholesterol acyltransferase. 

Apolipoprotein D, a glycoprotein referred to originally as thin-line polypeptide, is an apolipoprotein of Mr 22,700 found in HDL and VLDL (A6, L7, M2, M3). Kostner (K18) has described thin-line polypeptide, which he termed apoA-III. The amino acid composition of apoA-III differs from that described for apoD nevertheless, many workers have assumed that apoA-III is apoD. ApoA-III has been reported to be a potent activator of lecithimcholesterol acyltransferase (K17, 06), but apoD, though associated with LCAT (vide infra) appears not to activate the enzyme (A16). It appears quite possible, therefore, that apoD and apoA-III are different apolipoproteins. 

A12. Albers, J. J., Chen, C.-H., and Adolphson, J. L., Lecithimcholesterol acyltransferase (LCAT) mass its relationship to LCAT activity and cholesterol esterification rate. /. Lipid Res. 22, 1206-1213 (1981). 

B37. Blomhoff, J. P., Skrede, S., and Ritland, S., Lecithimcholesterol acyltransferase and plasma proteins in liver disease. Clin. Chim. Acta 53, 197-207 (1974). 

K19. Kostner, G., The influence of various lipoproteins and apolipoproteins on the in vitro esterification of cholesterol in human serum by the enzyme lecithimcholesterol acyltransferase. Scand. J. Clin. Lab. Invest. 38 (Suppl. 150), 66-71 (1978). 

R17, Rose, H. G., and Juliano, J., Regulation of plasma lecithimcholesterol acyltransferase in man. III. Role of high density lipoprotein cholesteryl esters in the activating effect of a high-fat test meal. J. Lipid Res. 20, 399-407 (1979). 

Sabesin, S. M., Hawkins, H. L., Kuiken, L., and Ragland, J. B., Abnormal plasma lipoproteins and lecithimcholesterol acyltransferase deficiency in alcoholic liver disease. Gastroenterology 72, 510-518 (1977). 

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