Biochim Biophys Acta. 2012 Jan 12;
Ng DS

Lecithin cholesterol acyltransferase (LCAT) is the key enzyme in mediating the esterification of cholesterol on circulating lipoproteins. It has long been suggested that LCAT plays a crucial role in reverse cholesterol transport, a process depicting the removal of cellular cholesterol through efflux to high density lipoproteins (HDL) and its delivery to the liver for eventual excretion from the body. Although loss-of-function LCAT mutations invariably result in profound HDL deficiency, the role of LCAT in atherogenesis continues to be clouded with controversy. Increasing number of large scale, population-based studies failed to detect an elevated cardiac risk with reduced blood levels of LCAT, suggesting that reduced LCAT activity may not be a risk factor nor a therapeutic target. More recent studies in human LCAT gene mutation carriers tend to suggest that atherogenicity in LCAT deficiency may be dependent on the nature of the mutations, providing plausible explanations for the otherwise contradictory findings. Genetic models of LCAT excess or deficiency yielded mixed findings. Despite it known profound effects on HDL and triglyceride metabolism, the role of LCAT in metabolic disorders, including obesity and diabetes, has not received much attention. Recent studies in LCAT deficient mouse models suggest that absence of LCAT may protect against insulin resistance, diabetes and obesity. Coordinated modulation of a number of anti-obesity and insulin sensitizing pathways has been implicated. Further studies to explore the role of LCAT in the modulation of cardiometabolic disorders and the underlying mechanisms are warranted.

Arch Intern Med. 2012 Jan 23; 172(2): 179-81
Simonelli S, Gianazza E, Mombelli G, Bondioli A, Ferraro G, Penco S, Sirtori CR, Franceschini G, Calabresi L

An antibody against the lecithin:cholesterol acyltransferase (LCAT) enzyme, which negates cholesterol esterification in plasma, causing severe high-density lipoprotein deficiency (HD), was identified in a woman with a large-cell non-Hodgkin lymphoma. Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of the defective cholesterol esterification and HD. To our knowledge, an acquired LCAT deficiency leading to severe HD has not been reported previously in association with a malignant disease, and this patient represents the first such documented case.

Atherosclerosis. 2011 Nov 28;
Calabresi L, Simonelli S, Gomaraschi M, Franceschini G

The lecithin:cholesterol acyltransferase (LCAT) enzyme is responsible for the synthesis of cholesteryl esters in human plasma and plays a critical role in high density lipoprotein (HDL) metabolism. Genetic LCAT deficiency is a rare metabolic disorder characterized by low HDL cholesterol levels. This paper reviews the genetic and biochemical features of LCAT deficiency, highlighting the absence of enhanced preclinical atherosclerosis in carriers, despite the remarkably low HDL cholesterol.

J Clin Lipidol. 2011 Nov; 5(6): 493-9
Roshan B, Ganda OP, Desilva R, Ganim RB, Ward E, Haessler SD, Polisecki EY, Asztalos BF, Schaefer EJ

A case of homozygous familial lecithin:cholesterol acyltransferase (LCAT) deficiency with a novel homozygous LCAT missense mutation (replacement of methionine by arginine at position 293 in the amino acid sequence of the LCAT protein) is reported.The probable diagnosis was suggested by findings of marked high density lipoprotein (HDL) deficiency, corneal opacification, anemia, and renal insufficiency. The diagnosis was confirmed by two dimensional gel electrophoresis of HDL, the measurement of free and esterified cholesterol, and sequencing of the LCAT gene.In our view the most important aspects of therapy to prevent the kidney disease that these patients develop is careful control of blood pressure and lifestyle measures to optimize non HDL lipoproteins. In the future replacement therapy by gene transfer or other methods may become available.

Clin Nephrol. 2011 Dec; 76(6): 492-8
Tsuchiya Y, Ubara Y, Hiramatsu R, Suwabe T, Hoshino J, Sumida K, Hasegawa E, Yamanouchi M, Hayami N, Marui Y, Sawa N, Hara S, Takaichi K, Oohashi K

We trace the 34-year history of a member of the first Japanese family in which lecithin-cholesterol acyltransferase (LCAT) deficiency was diagnosed. Marriage between cousins with low LCAT activity was responsible for familial LCAT deficiency (FLD). In 1976, a 27-year-old Japanese man was noted to have FLD based on proteinuria, hematuria, grayish corneal opacity and low LCAT activity (9.83%). Genetic analysis showed insertion of G-G-C coding glycine at codon 141. Total cholesterol (C) was low at 108 mg/dl and the ratio of C-ester to total C was very low (12%), while the lecithin (phosphatidylcholine) level was very high (97.3%). When his serum creatinine reached 2.6 mg/dl at the age of 41 years (in 1991), renal biopsy was performed. This showed expansion of the mesangial matrix and irregularly thickened capillary walls with a bubble-like appearance because of lipid deposits consisting of two components (partly lucent vacuolated areas and partly deeply osmiophilic areas). Magnification of the latter deposits showed curvilinear and serpiginous striated membranous structure. Hemodialysis was started in 1990 and has been continued for over 20 years until August 2010. Clinical problems have included AV shunt failure requiring 4 operations and 13 percutaneous transcatheter angioplasty procedures, as well as episodes of hemolytic anemia that subsided after infusion of fresh frozen plasma. Cardiovascular events have not yet occurred, although severe calcification of abdominal aorta has been detected by computed tomography.

Clin Nephrol. 2011 Oct; 76(4): 323-8
Shoji K, Morita H, Ishigaki Y, Rivard CJ, Takayasu M, Nakayama K, Nakayama T, Inoue Y, Ayaki M, Yoshimura A

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure. In all FLD cases, a mutation has been found in the coding sequence of the LCAT gene. FLD is clinically distinguished from an acquired form of LCAT deficiency by the presence of corneal opacities. Here we describe a 36-year-old woman presenting with clinical, pathological, and laboratory data compatible with FLD. Her mother and elder sister had corneal opacities. However, genetic analysis revealed there were no mutations in the LCAT coding sequences and no alterations in LCAT mRNA expression. Furthermore, we were unable to find any underlying conditions that may lead to LCAT deficiency. The present case therefore demonstrates that LCAT deficiency may be caused by factors other than mutations in the coding sequence and we suggest that a translational or posttranslational mechanism may be involved.

Cornea. 2012 Jan; 31(1): 55-8
Lisch W, Saikia P, Pitz S, Pleyer U, Lisch C, Jaeger M, Rohrbach JM

To demonstrate 5 different patterns of immunotactoid keratopathy (ITK) in monoclonal gammopathy of undetermined significance (MGUS) that can mimic hereditary and degenerative disorders. First follow-up of 1 female patient was performed.Colored slit-lamp photodocumentation of 6 MGUS light kappa patients with different types of ITK, one patient with a follow-up of 7 years. Systemic and serological examinations of all 6 patients were performed.The systemic and serological examinations disclosed an MGUS light kappa in all 6 patients. The 7-year follow-up of case 2 showed a reduction of lattice-like opacity to moderate diffuse corneal opacity. Corneal opacity patterns of the 6 patients were as follows: pattern 1, crystalline-like; pattern 2, lattice-like; pattern 3, peripheral granular-like; pattern 4, peripheral band-like; and patterns 5 and 6, peripheral patch-like.ITK of MGUS can mimic cystinosis, Schnyder corneal dystrophy (CD), pre-Descemet CD, lattice CD, granular CD, arcus lipoides, lecithin-cholesterol acyltransferase deficiency, gelatinous drop-like CD, and Salzmann nodular degeneration. ITK can be the first symptom of MGUS. An annual internal check of MGUS is recommended because of occurrence of a systemic monoclonal gammopathy in 20% of cases.

Hum Mutat. 2011 Nov; 32(11): 1290-8
Holleboom AG, Kuivenhoven JA, Peelman F, Schimmel AW, Peter J, Defesche JC, Kastelein JJ, Hovingh GK, Stroes ES, Motazacker MM

Lecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high-density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL-cholesterol (HDL-c) deficiency while heterozygotes have half normal HDL-c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL-c to better understand the molecular basis of low HDL-c in our patients. LCAT was sequenced in 98 patients referred for HDL-c <5th percentile and in four patients referred for low HDL-c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal opacity were compound heterozygotes. All previously identified mutations are documented to cause loss of catalytic activity. Nine novel mutations-c.402G>T (p.E134D), c.403T>A (p.Y135N), c.964C>T (p.R322C), c.296G>C (p.W99S), c.736G>T (p.V246F), c.802C>T (p.R268C), c.945G>A (p.W315X), c.1012C>T (p.L338F), and c.1039C>T (p.R347C)--were shown to be functional through in vitro characterization. The effect of several mutations on the core protein structure was studied by a three-dimensional (3D) model. Unlike previous reports, functional mutations in LCAT were found in 29% of patients with low HDL-c, thus constituting a common cause of low HDL-c in referred patients in The Netherlands.

G Ital Nefrol. 2011 Jul-Aug; 28(4): 369-82
Boscutti G, Calabresi L, Pizzolitto S, Boer E, Bosco M, Mattei PL, Martone M, Milutinovic N, Berbecar D, Beltram E, Franceschini G

A genetic mendelian autosomal recessive condition of deficiency of lecithin- cholesterol acyltransferase (LCAT) can produce two different diseases: one highly interesting nephrologic picture of complete enzymatic deficiency (lecithin:cholesterol acyltransferase deficiency; OMIM ID #245900; FLD), characterized by the association of dyslipidemia, corneal opacities, anemia and progressive nephropathy; and a partial form (fish eye disease; OMIM ID #136120; FED) with dyslipidemia and progressive corneal opacities only. The diagnosis of FLD falls first of all under the competence of nephrologists, because end-stage renal disease appears to be its most severe outcome. The diagnostic suspicion is based on clinical signs (corneal opacities, more severe anemia than expected for the degree of chronic renal failure, progressive proteinuric nephropathy) combined with histology obtained by kidney biopsy (glomerulopathy evolving toward sclerosis with distinctive lipid deposition). However, the final diagnosis, starting with a finding of extremely low levels of HDL-cholesterol, requires collaboration with lipidology Centers that can perform sophisticated investigations unavailable in common laboratories. To be heterozygous for a mutation of the LCAT gene is one of the monogenic conditions underlying primary hypoalphalipoproteinemia (OMIM ID #604091). This disease, which is characterized by levels of HDL-cholesterol below the 5th percentile of those of the examined population (<28 mg/dL for Italians), has heritability estimates between 40% and 60% and is considered to be a predisposing condition for coronary artery disease. Nevertheless, some monogenic forms, and especially those associated with LCAT deficiency, seem to break the rule, confirming once more the value of a proper diagnosis before drawing prognostic conclusions from a laboratory marker. As in many other rare illnesses, trying to discover all the existing cases will contribute to allow studies broad enough to pave the way for further therapies, in this case also fostering the production by industries of the lacking enzyme by genetic engineering. Epidemiological studies, although done on selected populations such as hypoalphalipoproteinemia patients on dialysis and with the effective genetic tools of today, have been disappointing in elucidating the disease. Spreading the clinical knowledge of the disease and its diagnostic course among nephrologists seems to be the best choice, and this is the aim of our work.

J Atheroscler Thromb. 2011; 18(8): 713-9
Wang XL, Osuga J, Tazoe F, Okada K, Nagashima S, Takahashi M, Ohshiro T, Bayasgalan T, Yagyu H, Okada K, Ishibashi S

Lecithin-cholesterol acyltransferase (LCAT) is an important enzyme involved in the esterification of cholesterol. Here, we report a novel point mutation in the LCAT gene of a 63-year-old female with characteristics of classic familial LCAT deficiency. The patient's clinical manifestations included corneal opacity, mild anemia, mild proteinuria and normal renal function. She had no sign of coronary heart disease. Her LCAT activity was extremely low. DNA sequencing revealed a point mutation in exon 5 of the LCAT gene: a G to C substitution converting Gly(179) to an Arg, located in one of the catalytic triads of the enzyme. In vitro expression of recombinant LCAT proteins in HEK293 cells showed that the mutant G179R protein was present in the cell lysate, but not the culture medium. LCAT activity was barely detectable in the cell lysate or medium of the cells expressing the G179R mutant. This novel missense mutation seems to cause a complete loss of catalytic activity of LCAT, which is also defective in secretion.

Proc Natl Acad Sci U S A. 2011 May 24; 108(21): 8879-84
Zhang T, Zhang N, Baehr W, Fu Y

Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat(-)(/-), a murine model for LCA, to investigate the mechanism of rapid cone degeneration. Although both M and S cone opsins mistrafficked as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat(-)(/-) cones before the onset of massive ventral/central cone degeneration. As the ventral and central retina express higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65(-)(/-) and Lrat(-)(/-) LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in patients with LCA. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an endoplasmic reticulum stress pathway, as demonstrated in both the Lrat(-)(/-) retina and transfected cells. Replacing rhodopsin with S-opsin in Lrat(-)(/-) rods resulted in mislocalization and aggregation of S-opsin in the inner segment and the synaptic region of rods, ER stress, and dramatically accelerated rod degeneration. Our results demonstrate that cone opsins play a major role in determining the degeneration rate of photoreceptors in LCA.

Invest Ophthalmol Vis Sci. 2011 Jul; 52(8): 5507-14
Hu Y, Chen Y, Moiseyev G, Takahashi Y, Mott R, Ma JX

RPE65 gene knockout (Rpe65⁻/⁻) mice showed abolished isomerohydrolase activity in the visual cycle and were considered a model for vitamin A deficiency in the retina. The purpose of this study was to compare the retinal phenotypes between vitamin A-deficient (VAD) mice and Rpe65⁻/⁻ mice under normal diet.The VAD mice were fed with a vitamin A-deprived diet after birth. The age-matched control mice and Rpe65⁻/⁻ mice were maintained under normal diet. The structure of photoreceptor outer segment was compared using electron microscopy. Photoreceptor-specific gene expression was determined using real-time RT-PCR. The isomerohydrolase and lecithin-retinol acyltransferase (LRAT) activities were measured using an in vitro enzymatic activity assay. Endogenous retinoid profiles were analyzed by HPLC in mouse eyecup homogenates.Compared to wild-type mice under normal diet, scanning and transmission electron microscopy showed that the outer segments of photoreceptors were disorganized in VAD mice and were not disorganized in Rpe65⁻/⁻ mice, although they were shortened in the latter. VAD mice showed more prominent downregulation of middle wavelength cone opsin, whereas Rpe65⁻/⁻ mice displayed more suppressed expression of short wavelength cone opsin. In vitro enzymatic activity assay and Western blot analysis showed that vitamin A deprivation downregulated LRAT expression and activity in the eyecup, but Rpe65⁻/⁻ mice showed unchanged LRAT expression and activity. The depressed LRAT activity in VAD mice was partially rescued by the intraperitoneal injection of retinoic acid.VAD and Rpe65⁻/⁻ mice are different in cone photoreceptor degeneration, photoreceptor-specific gene regulation, isomerohydrolase activity, endogenous retinoid profile, and LRAT activity.