LCAT deficiency

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). 

The presence of LP-X in the plasma of patients with liver disease has been considered as a sensitive indicator of biliary obstruction and, thus, useful in the differential diagnosis of diseases of the liver (S29, Wl). However, the recent demonstration (see Section 8.2) that particles resembling LP-X occur also in the plasma of patients with LCAT deficiency poses serious reservations regarding the specificity of the proposed test. 

Familial LCAT deficiency, an inborn error of metabolism that affects the levels of plasma cholesteryl esters, was recently discovered in Scandinavia (G7, G8, G9, GIO, Gll, N4). Patients with this disease have... 

One of the most striking lipoprotein abnormalities of familial LCAT deficiency is the presence in the LDL fraction of abnormally large particles, containing variable but unusually great proportions of unesteri-fied cholesterol and lecithin (F6, G14, N5). Recently, an abnormal LDL lipoprotein, identical to cholestatic lipoprotein, LP-X (see Section 8.1) was demonstrated in plasma from patients with familial LCAT deficiency (Ml, T2). Identity of the abnormal LDL lipoprotein and LP-X was shown by electron microscopy, composition, and immunological techniques (T2). The amount of LP-X in plasma of patients with obstructive jaundice ranged from 40 to 1200 mg/100 ml (M3) whereas plasma from patients with familial LCAT deficiency contained 49 to 152 mg/100 ml (T2). 

It remains to be demonstrated whether all of the abnormalities of patients lipoproteins can be explained on the basis of LCAT deficiency or whether other secondary factors play a role in this disease. 

LCAT catalyzes the transfer of a preferentially unesterified fatty acid from the sn-2 position of phosphatidylcholine to the 3/i-hydroxy group of cholesterol, and thereby produces lysophosphatidylcholine and a cholesteryl ester [50]. Depending on the mutation in the LCAT gene, homozygous or compound heterozygous patients present with one of two clinical phenotypes, classical LCAT deficiency or fish-eye disease [58, 85]. Classical LCAT deficiency is caused by a broad spectrum of missense and non-sense mutations that interfere with the synthesis or secretion or affect the catalytic activity of LCAT [10]. Fish-eye disease is caused by a limited number of missense point mutations that alter the surface polarity, and thereby interfere with the binding of the enzyme to apoA-I containing lipoproteins [77]). 

Homozygotes or compound heterozygotes are characterized by the occurrence of corneal cloudings, which after the third decade become apparent upon physical examination. In addition, patients with classical LCAT deficiency develop renal disease with proteinuria and hematuria, which progresses to terminal renal insufficiency and hemolytic anemia [58,85]. 

Biochemically, both patients with classical LCAT deficiency and fish-eye disease present with very low levels of HDL cholesterol (< 0.3 mmol/1), although some pa-... 

LCAT acts preferentially on lipids transported by HDL (so-called a-LCAT activity), but also on lipids transported by apoB-containing lipoproteins (so-called jS-LCAT activity) [58, 85]. In practice, LCAT activity is measured either as the activity required to esterify radioactive cholesterol that has been exogenously incorporated into native HDL or into artificial HDL-like particles (a-LCAT activity) or which has been equilibrated with endogenous lipoproteins of the plasma sample (cholesterol esterification rate, CER) [21, 58, 85]. Several variations of these assays have been reported, some of which are available as commercial test kits (e.g., Roar Biomedical, New York, USA). In addition, LCAT concentration can be determined by either laboratory-made tests or by a commercial ELISA kits [57]. However, the decrease in LCAT concentration is difficult to judge since it also decreases secondary to HDL deficiency due to causes other than LCAT deficiency. Plasma from patients with LCAT deficiency fails to esterify radioactive cholesterol provided by any substrate. By contrast, plasmas of patients with fish-eye disease show a near-normal cholesterol ester-fication rate but have a selective inability to esterify radioactive cholesterol provided to plasma with native HDL or reconstituted HDL (a-LCAT activity) [58, 85]. 

Patients with classical LCAT deficiency fail to esterify cholesterol in any substrate and hence have both an undetectable or very low cholesterol esterification rate and a-LCAT activity. Patients with fish-eye disease usually have a normal cholesterol esterification rate and a selective a-LCAT deficiency. 

Considerable amounts of LCAT are carried by HDL therefore a-LCAT activity is also secondarily reduced in other forms of familial HDL deficiency. Notably, this partial LCAT deficiency has been repeatedly documented in forms of apoA-I deficiency due to structural defects in apoA-I. However, despite secondary LCAT deficiency these patients have a normal unesterified cholesterolitotal cholesterol ratio [35]. 

Patients with classical LCAT deficiency show an increased proportion of unesterified cholesterol in plasma (80-100%). By contrast, the plasma from patients with fish-eye disease has a slightly elevated proportion of unesterified cholesterol (up to 70%). 

Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J (1997) The molecular pathology of lecith in cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res 38 191-205... 

I. LCAT deficiency. Cholesterol associated with HDL cannot be esterified. There is a buildup of unesterified cholesterol, with comeal opacities, renal insufficiency, hemolytic anemia, and premature atherosclerosis. The diagnosis may be made on enzyme assay for plasma LCAT. 

Kuivenhoven, J., Pritchard, H., Hill, J-, Frohlich, J., Assman, G.,and Kastelein, J. (1997). The molecular pathology of lecithin Cholesterol acyltransferase (LCAT) deficiency syndromes. J. Lipid Res. 38,191-205. 

Lipoprotein-X (Lp-X), an abnormal lipoprotein, occurs in patients with obstructive liver disease or LCAT deficiency. Lp-X floats in the density range of LDL and has the same electrophoretic mobility as LDL. It can be separated from LDL, however, by hydroxyapatite chromatography or by zonal centrifugation. The composition of Lp-X differs from that of LDL, and it does not react with antisera to LDL. The major apoproteins of Lp-X isolated from patients with LCAT deficiency are albumin, apo C, and apo A. Lp-X also contains small amounts of apo D and apo E. Lp-X from patients with obstructive liver disease has been reported to lack apo A-I, a powerful activator of LCAT. The lipid constituents of Lp-X are cholesterol (almost entirely unesterified) and phospholipids. In electron microscopy, negatively stained Lp-X preparations appear as stacks of disk-like structures rouleaux). 

LCAT deficiency is due either to absence of the enzyme or to synthesis of defective enzyme. LCAT catalyzes the following reaction ... 

Rare forms of lipoprotein disorders may include hypobeta-lipoproteinemia, abetalipoproteinemia, Tangier disease, LCAT deficiency (fish-eye disease), cerebrotendinous xanthomatosis (CTX),... 

The significance of the complex sequence of events involved in the formation, transfer, and clearance of plasma lipoprotein CE is demonstrated dramatically by several inborn errors of metabolism. One such error is familial LCAT deficiency [67]. In this disease, as well as in diseases associated with acquired LCAT deficiency, LCAT activity in the plasma is abnormally low, and many hpoprotein and tissue abnormalities are observed. The content of UC and PC is abnormally high, and the molar ratio of UC to PC in the hpoproteins is also high, sometimes reaching a value of nearly 2 1. In association with these abnormahties, most lipoproteins show an abnormally low content of CE. In addition, there are abnormahties in the distribution and/or concentration of apolipoproteins AI, All, B, C, and E disc-shaped HDL and unusually small spherical HDL are seen and multilamehar vesicles containing UC and PC are usually present in the LDL fraction obtained by preparative ultracentrifugation. These abnormahties all seem to depend on the LCAT deficiency they are altered toward normal when patient plasma is incubated with LCAT in vitro. 

The best understood of the tissue abnormahties that typically accompany familial LCAT deficiency involves the erythrocytes. The latter contain up to twice the normal amount of UC as weh as increased amounts of PC. They have an abnormal, target cell shape, and there is evidence for both increased hemolysis and inadequate erythrocyte formation. These abnormalities probably depend on the LCAT de-... 

Whether LCAT deficiency leads to an increased content of UC in all cell plasma membranes is not yet clear, but analyses of tissues obtained from the patients have revealed increased contents of UC in the liver, kidneys, spleen, and arteries [67], Meanwhile, there are granular deposits in the cornea that seem to consist of lipid, and foam cells that seem to contain CE are seen in the bone marrow, spleen, and glomerular tufts of the kidney. The kidney abnormalities may be of special significance because renal dysfunction can be a life-threatening feature of the disease. Proteinuria is detectable in childhood, and sometimes progresses to renal failure later on in life. 

Though many of these tissue abnormalities remain to be explained, the totality of the abnormalities seen in familial LCAT deficiency provides striking evidence for the importance of the LCAT reaction in plasma lipoprotein metabolism, emd shows how failure to form CE in the plasma can influence the composition and function of tissues. The possibihty that renal glomeruli are particularly sensitive to the composition of plasma lipoproteins clearly deserves to be explored. 

The purification and properties of LCAT, together with a discussion of its mechanism of reaction are given by Marcel (1982). A number of disease states involve LCAT activity. Familial LCAT deficiency has been described (Glomset and Norum, 1973) and patients with this rare complaint have been thoroughly investigated. Many of the abnormalities seem in such patients have been found in those with cholestasis also. A discussion of cholesterol ester metabolism in relation to other liver diseases and dyslipoproteinaemia has been reported (Marcel, 1982). Similarly, the metabolism of cholesterol esters in relation to arteries and arterial disease has been fully discussed (Kritchevsky and Kothari, 1978). Mammalian steroid sulphates have been reviewed by Farooqui (1981). 

LCAT deficiency in LDLr-/- mice and Apo E -/- mice fed an atherogenic diet, resulted in aortic cholesterol deposition likely caused by a reduction in plasma HDL, increased saturation of CE in apo B lipoproteins, and in the Apo E -/- background, increased plasma Apo B lipoprotein concentration (470). LCAT-deficient mice are associated with an increase in oxidative stress that is paradoxically reversed in a hyperlipidemic background possibly caused by the redistribution of paraoxonase (PON) to the non-HDL fraction. This may in part contribute to the reduced atherosclerosis seen in Apo E -/- xLCAT -/- mice (this could explain the surprising finding that LCAT-deficient subjects have severe hypoalphalipoproteinemia yet are not prone to premature CHD) (477). 

LCAT deficiency (complete) Lecithin cholesterol acyltransferase (LCAT) Liver 16q22 245900... 

Fig. 28.1. A schematic diagram depicting lipoprotein metabolism and the known genetic defects affecting lipoproteins. 28.1, Lipoprotein lipase (LPL) deficiency 28.2, apoC-II deficiency 28.3, apoE deficiency or mutations 28.4, hepatic lipase (HL) deficiency 28.5, LDL receptor deficiency or mutations 28.6, apoB-100 mutation in receptor binding region 28.7, apoA-I deficiency or mutations 28.7.3, ABCAl deficiency or mutations 28.8, LCAT deficiency 28.9, microsomal transfer protein (MTP) deficiency 28.10, apoB-100 synthesis or truncation mutations. Abbreviations C-II, apoC-II B, apoB E, apoE A-I, apoA-I VLDL, very-low-density lipoproteins IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LPL, lipoprotein lipase HL, hepatic lipase LCAT, lecithin cholesterol acyltransferase UC, unesterified cholesterol...

Table 28.8.2. Partial LCAT deficiency (Fish-eye disease) ...

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