Classic (complete) lecithin:cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels ofapoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-1

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Lipid trafficking in the brain is essential for the maintenance and repair of neuronal membranes, especially after neurotoxic insults. However, brain lipid metabolism is not completely understood. In plasma, LCAT catalyses the esterification of free cholesterol on circulating lipoproteins, a key step in the maturation of HDL. Brain lipoproteins are apolipoprotein E (apoE)-containing, HDL-like particles secreted initially as lipid-poor discs by glial cells. LCAT is synthesized within the brain, suggesting that it may play a key role in the maturation of these lipoproteins. Here we demonstrate that astrocytes are the primary producers of brain LCAT. This LCAT esterifies free cholesterol on nascent apoE-containing lipopoproteins secreted from glia. ApoE is the major LCAT activator in glia-conditioned media (GCM), and both the cholesterol transporter ABCA1 and apoE are required to generate glial LCAT substrate particles. LCAT deficiency leads to the appearance of abnormal ?8 nm particles in GCM, and exogenous LCAT restores the lipoprotein particle distribution to the wild-type (WT) pattern. In vivo, complete LCAT deficiency results in a dramatic increase in apoE-HDL and reduced apolipoprotein A-I (apoA-I)-HDL in murine cerebrospinal fluid (CSF). These data show that brain LCAT esterifies cholesterol on glial-derived apoE-lipoproteins, and influences CSF apoE and apoA-I levels. In plasma, LCAT is the sole enzyme capable of esterifying cholesterol in the circulation. LCAT is a 416 amino acid protein that circulates in plasma predominately bound to lipoproteins, where it catalyses the transfer of an unsaturated fatty acid from phosphatidylcholine, or lecithin, to the free b-hydroxyl residue of cholesterol to generate cholesterol esters (CE) and lysoPC (lysolecithin) (1). Esterification of lipoprotein cholesterol results in the segregation of CE into the lipoprotein core, an essential step in peripheral HDL maturation. Mutations in the human LCAT gene underlie two distinct metabolic diseases, Familial LCAT Deficiency and Fish Eye Disease, both of which present with low HDL levels (2).The preferred plasma substrate for circulating LCAT is free cholesterol found on HDL, and apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is considered the major physiological activator of LCAT (3). In vitro experiments show that other plasma apolipoproteins, including apolipoprotein E (apoE), apoC-I, and apoA-IV, are capable of activating LCAT, albeit less efficiently than apoA-I (3). Moreover, apoA-I, and to a lesser extent, apoE appear to be the predominant in vivo activators of LCAT, as a recent analysis of apoA-I-, apoE-, and double apoA-I/ apoE-deficient mice shows that the percentage of free cholesterol esterified in plasma drops to less than 2% of wildtype (WT) values after deletion of apoA-I and apoE (4).LCAT is synthesized mainly in liver, but is also abundant in brain and testes (5-8). Indeed, brain exhibits the second highest LCAT mRNA level after liver in rats and rhesus monkeys (6, 9). Brain LCAT ...

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Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatment, patients develop severe hypocholesterolemia along with striking alterations in the concentration and composition of the circulating lipoproteins. The present study was undertaken to gather information about the pathogenesis of these abnormalities. Patients were studied before-, during- and after a 5-day course of high dose i.v. rIL-2. Whole plasma cholesterol was markedly reduced by rIL-2 administration (52%; P < 0.001), whereas the triglyceride concentration did not change. Thus, the lipoproteins became triglyceride enriched (P = 0.004). Low density lipoprotein cholesterol, apolipoprotein B (apoB), high density lipoprotein cholesterol, and apoA-I concentrations all decreased. Esterified cholesterol levels were markedly reduced. Total plasma apoE increased markedly, and two kinds of abnormal particles appeared: 1) beta-migrating, very low density lipoproteins; and 2) discoidal, apoE- and phospholipid-containing particles with abnormal density and electrophoretic mobility. The activities of two lipoprotein triglyceride hydrolases, lipoprotein lipase and hepatic lipase, fell significantly during treatment and returned promptly to pretreatment levels after rIL-2 was discontinued. Lecithin:cholesteryl acyltransferase (LCAT) activity also decreased significantly (64%) during treatment, but in contrast to the lipases, remained low for at least 5 days after the last dose of rIL-2 (P < 0.001). High dose i.v. rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency. Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis.