Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator.

Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/ß-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.

Rapidly progressive renal failure to reveal LCAT deficiency in an Algerian family.

Lecithin-cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder that can reveal two different diseases: a very interesting nephrological picture of complete enzyme deficiency characterized by the association of dyslipidemia, corneal opacities, anemia, and progressive nephropathy; and a partial form (fish-eye disease) with dyslipidemia and progressive corneal opacities only. We report herein the case of a 35-year-old man who presented hypertension, renal symptomatology of rapidly progressive glomerulonephritis associates: nephrotic proteinuria, severe renal failure, in combination with annular corneal opacities, anemia, and dyslipidemia. The diagnosis of familial LCAT deficiency was confirmed by clinical examination, characteristic dyslipidemia, undetectable LCAT levels in plasma, and positive family history.

A systematic review of the natural history and biomarkers of primary lecithin:cholesterol acyltransferase deficiency.

Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.

Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans.

Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0-37.8] mg/dl) and slightly reduced in heterozygotes (218 [153-234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2.

Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report.

[Figure: see text].

Spontaneous Atherosclerosis in Aged LCAT-Deficient Hamsters With Enhanced Oxidative Stress-Brief Report.

OBJECTIVE: LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT-/-) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT-/- hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results: Young (<8 months) and aged (>16 months) male and female wild-type and LCAT-/- hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT-/- hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT-/- hamsters, the lesion areas at the aortic roots were ≈40×104 µm3 in males and 18×104 µm3 in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 µmol/L in males and 30 µmol/L in females, which are significantly associated with the atherosclerotic lesions. CONCLUSIONS: Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT-/- hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.

LCAT deficiency: a systematic review with the clinical and genetic description of Mexican kindred.

BACKGROUND: LCAT (lecithin-cholesterol acyltransferase) deficiency is characterized by two distinct phenotypes, familial LCAT deficiency (FLD) and Fish Eye disease (FED). This is the first systematic review evaluating the ethnic distribution of LCAT deficiency, with particular emphasis on Latin America and the discussion of three Mexican-Mestizo probands. METHODS: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) Statement in Pubmed and SciELO. Articles which described subjects with LCAT deficiency syndromes and an assessment of the ethnic group to which the subject pertained, were included. RESULTS: The systematic review revealed 215 cases (154 FLD, 41 FED and 20 unclassified) pertaining to 33 ethnic/racial groups. There was no association between genetic alteration and ethnicity. The mean age of diagnosis was 42 ± 16.5 years, with fish eye disease identified later than familial LCAT deficiency (55 ± 13.8 vs. 41 ± 14.7 years respectively). The prevalence of premature coronary heart disease was significantly greater in FED vs. FLD. In Latin America, 48 cases of LCAT deficiency have been published from six countries (Argentina (1 unclassified), Brazil (38 FLD), Chile (1 FLD), Columbia (1 FLD), Ecuador (1 FLD) and Mexico (4 FLD, 1 FED and 1 unclassified). Of the Mexican probands, one showed a novel LCAT mutation. CONCLUSIONS: The systematic review shows that LCAT deficiency syndromes are clinically and genetically heterogeneous. No association was confirmed between ethnicity and LCAT mutation. There was a significantly greater risk of premature coronary artery disease in fish eye disease compared to familial LCAT deficiency. In FLD, the emphasis should be in preventing both cardiovascular disease and the progression of renal disease, while in FED, cardiovascular risk management should be the priority. The LCAT mutations discussed in this article are the only ones reported in the Mexican- Amerindian population.

Genetic, biochemical, and clinical features of LCAT deficiency: update for 2020.

PURPOSE OF REVIEW: Genetic LCAT deficiency is a rare metabolic disorder characterized by low-plasma HDL cholesterol levels. Clinical manifestations of the disease include corneal opacification, anemia, and renal disease, which represents the major cause of morbidity and mortality in carriers. RECENT FINDINGS: Biochemical and clinical manifestations of the disease are very heterogeneous among carriers. The collection of large series of affected individuals is needed to answer various open questions on this rare disorder of lipid metabolism, such as the cause of renal damage in patients with complete LCAT deficiency and the cardiovascular risk in carriers of different LCAT gene mutations. SUMMARY: Familial LCAT deficiency is a rare disease, with serious clinical manifestations, which can occur in the first decades of life, and presently with no cure. The timely diagnosis in carriers, together with the identification of disease biomarkers able to predict the evolution of clinical manifestations, would be of great help in the identification of carriers to address to future available therapies.

Complete and Partial Lecithin:Cholesterol Acyltransferase Deficiency Is Differentially Associated With Atherosclerosis.

BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) is the sole enzyme that esterifies cholesterol in plasma. Its role in the supposed protection from atherogenesis remains unclear because mutations in LCAT causing fish-eye disease (FED) or familial LCAT deficiency (FLD) have been reported to be associated with more or instead less carotid atherosclerosis, respectively. This discrepancy may be associated with the loss of cholesterol esterification on only apolipoprotein AI (FED) or on both apolipoprotein AI- and apolipoprotein B-containing lipoproteins (FLD), an aspect that has thus far not been investigated. METHODS: Seventy-four heterozygotes for LCAT mutations recruited from Italy and the Netherlands were assigned to FLD (n=33) or FED (n=41) groups and compared with 280 control subjects. Subclinical atherosclerosis was assessed with carotid intima-media thickness. RESULTS: Compared with control subjects, total cholesterol was lower by 16% (-32.9 mg/dL) and 7% (-14.9 mg/dL) and high-density lipoprotein cholesterol was lower by 29% (-16.7 mg/dL) and 36% (-20.7 mg/dL) in the FLD and FED groups, respectively. Subjects with FLD displayed a significant 18% lower low-density lipoprotein cholesterol compared with subjects with FED (101.9±35.0 versus 123.6±47.4 mg/dL; P=0.047) and control subjects (122.6±35.0 mg/dL; P=0.003). Remarkably, all 3 intima-media thickness parameters were lower in subjects with FLD compared with FED and control subjects (accounting for age, sex, body mass index, smoking, hypertension, family history of cardiovascular disease, and plasma lipids). After additional correction for nationality and ultrasonographic methods, average and maximum intima-media thickness remained significantly lower when subjects with FLD were compared with those with FED (0.59 versus 0.73 mm, P=0.003; and 0.87 versus 1.24 mm, P<0.001, respectively). In contrast, the common carotid intima-media thickness (corrected for age, sex, body mass index, smoking, hypertension, family history of cardiovascular disease, and plasma lipids) was higher in subjects with FED compared with control subjects (0.69 versus 0.65 mm; P=0.05), but this significance was lost after adjustment for nationality and ultrasonographic machine. CONCLUSIONS: In this head-to-head comparison, FLD and FED mutations were shown to be associated with decreased and increased atherosclerosis, respectively. We propose that this discrepancy is related to the capacity of LCAT to generate cholesterol esters on apolipoprotein B-containing lipoproteins. Although this capacity is lost in FLD, it is unaffected in FED. These results are important when considering LCAT as a target to decrease atherosclerosis.

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred.

RATIONALE & OBJECTIVE: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. PREDICTORS: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. OUTCOMES: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. ANALYTICAL APPROACH: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. RESULTS: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. LIMITATIONS: The presence of cardiovascular disease was mainly based on medical history. CONCLUSIONS: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.

Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia.

BACKGROUND: Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia, among other lipid-related traits. Our aim is to evaluate clinical/biochemical features of a Chilean family with a proband showing clinical signs of familial LCAT deficiency, as well as to identify and assess the functional effects of LCAT mutations. METHODS: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239 T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In-silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. RESULTS: LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband's plasma, but with undetectable enzyme activity compared to control relatives. HEK-293 T transfected cells with vector expression plasmids containing either p.M404 V or p.V333 M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Additionally, the proband carried the minor allele of the synonymous p.L363 L variant. However, this variant is unlikely to affect the clinical phenotype of the proband given its relatively high frequency in the Chilean population (4%) and its small putative effect on plasma HDL-cholesterol levels. CONCLUSION: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404 V and p.V333 M in LCAT gene lead to suppression of LCAT enzyme activity and cause clinical features of familial LCAT deficiency.

Cellular cholesterol accumulation modulates high fat high sucrose (HFHS) diet-induced ER stress and hepatic inflammasome activation in the development of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development. Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet-induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitate-induced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol-focused strategy for treatment of NASH.

Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency Promotes Differentiation of Satellite Cells to Brown Adipocytes in a Cholesterol-dependent Manner.

Our laboratory previously reported that lecithin:cholesterol acyltransferase (LCAT) and LDL receptor double knock-out mice (Ldlr(-/-)xLcat(-/-) or DKO) spontaneously develop functioning ectopic brown adipose tissue (BAT) in skeletal muscle, putatively contributing to protection from the diet-induced obesity phenotype. Here we further investigated their developmental origin and the mechanistic role of LCAT deficiency. Gene profiling of skeletal muscle in DKO newborns and adults revealed a classical lineage. Primary quiescent satellite cells (SC) from chow-fed DKO mice, not in Ldlr(-/-)xLcat(+/+) single-knock-out (SKO) or C57BL/6 wild type, were found to (i) express exclusively classical BAT-selective genes, (ii) be primed to express key functional BAT genes, and (iii) exhibit markedly increased ex vivo adipogenic differentiation into brown adipocytes. This gene priming effect was abrogated upon feeding the mice a 2% high cholesterol diet in association with accumulation of excess intracellular cholesterol. Ex vivo cholesterol loading of chow-fed DKO SC recapitulated the effect, indicating that cellular cholesterol is a key regulator of SC-to-BAT differentiation. Comparing adipogenicity of Ldlr(+/+)xLcat(-/-) (LCAT-KO) SC with DKO SC identified a role for LCAT deficiency in priming SC to express BAT genes. Additionally, we found that reduced cellular cholesterol is important for adipogenic differentiation, evidenced by increased induction of adipogenesis in cholesterol-depleted SC from both LCAT-KO and SKO mice. Taken together, we conclude that ectopic BAT in DKO mice is classical in origin, and its development begins in utero. We further showed complementary roles of LCAT deficiency and cellular cholesterol reduction in the SC-to-BAT adipogenesis.

Familial Lecithin Cholesterol Acyl Transferase Deficiency with Chronic Kidney Disease.

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive (AR) disease caused by mutation in the LCAT gene. LCAT enzyme esterifies cholesterol molecules in high-density lipoprotein(HDL) and low density-lipoprotein (LDL) particles. This enzyme deficiency is characterised by progressive corneal opacification, glomerulopathy, mild - moderate haemolytic anaemia and very low plasma levels of HDL. We here report a 34 year-old lady who presented with hypertension, nephrotic proteinuria, renal failure, corneal ring opacities, anemia and dyslipidemia. The diagnosis of familial LCAT deficiency was confirmed by clinical examination, characteristic dyslipidemia, undetectable LCAT levels in plasma and positive family history.

Lipoprotein subfractions highly associated with renal damage in familial lecithin:cholesterol acyltransferase deficiency.

OBJECTIVE: In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. APPROACH AND RESULTS: Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large low-density lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. CONCLUSIONS: Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED. The abnormal lipoproteins were sensitive to treatment with recombinant LCAT and thus may play a causal role in the renal pathology of FLD.

LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice.

A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating ß-amyloid (Aß) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aß clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aß or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aß clearance.

Longitudinal analysis of clinical and laboratory biomarkers in a patient with familial lecithin: cholesterol acyltransferase deficiency (FLD) and accelerated eGFR decline: A case study.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations. Results show that elevated triglyceride and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.

A Novel Symptomatic Lecithin-Cholesterol Acyltransferase Gene Mutation With Corneal Amyloidosis.

PURPOSE: To present ocular clinical, histological, systemic, and genetic findings of a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency caused by a novel genetic variant of the LCAT gene associated with secondary corneal amyloidosis. METHODS: Case report. RESULTS: A 74-year-old woman presented with decreased visual acuity (VA), sensitivity to light, and progressive whitening of both corneas for approximately 20 years. The patient had undergone penetrating keratoplasty (PKP) on the right eye 6 years ago. Ophthalmologic examination revealed decreased VA in both eyes (OD: 0.05, OS: 0.3), and even further reduced glare VA (OD: 0.05, OS: 0.1), diffuse whitish corneal opacity involving the total thickness of the corneal stroma without crystalline deposits, and a marked peripheral diffuse arcus. Systemic examination revealed severely reduced plasma high-density lipoprotein cholesterol levels, target cells in blood smear, and chronic normochromic anemia. Clinically, LCAT deficiency was the most likely diagnosis. Further genetic analysis confirmed the diagnosis. The patient is homozygous for the novel variant c.943T>C (p.Trp315Arg) in the LCAT gene. Histologic examination of the cornea removed during the first keratoplasty revealed amyloid deposits. The cornea removed at the second keratoplasty had small vacuoles in the anterior stroma, indicating recurrence of lipid deposition. CONCLUSIONS: LCAT deficiency is a rare genetic disorder that can cause corneal opacities because of lipid deposition in the cornea. Systemic manifestations may help in the differential diagnosis to other diseases associated with severe high-density lipoprotein cholesterol reduction. Genetic analysis is employed to confirm the diagnosis. Some mutations in the LCAT gene seem to be associated with secondary corneal amyloidosis. Further investigation of this association is warranted. A recurrence of corneal opacity after PKP seems to occur mainly in the anterior corneal stroma.

Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice.

We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr-/-xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr-/-xLcat-/- mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr-/-xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr-/-xLcat-/- mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr-/-xLcat-/- mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr-/-xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD-fed Ldlr-/-xLcat-/- mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance.