レシチンコレステロールアシルトランスフェラーゼ欠損症

BACKGROUND: Apo (apolipoprotein) AI glycation has been implicated in HDL (high-density lipoprotein) dysfunction, but its site-resolved landscape, clinical relevance, relationship with diabetic atherosclerosis, and underlying mechanisms remain incompletely defined. METHODS: We performed unbiased site-resolved glycation proteomics in 860 patients with type 2 diabetes and coronary atherosclerosis (CAS) and 294 controls with type 2 diabetes without CAS to define the plasma apo AI glycation landscape. Apo AI glycation signatures associated with diabetic CAS were identified using integrated unsupervised and supervised analyses. An Apo AI Glycation Index was developed using least absolute shrinkage and selection operator regression and evaluated in training, testing, and independent validation cohorts. To assess functional relevance, a glycation-resistant apo AI mutant, cross-linked apo AI (apo AICL), was engineered and tested under glycation conditions using surface plasmon resonance, in vitro and in vivo reverse cholesterol transport assays, HDL remodeling analyses, and atherosclerosis models. RNA sequencing, macrophage-specific knockout models, receptor-binding assays, signaling inhibition, and cholesterol efflux rescue experiments were used to investigate the underlying macrophage pathway. RESULTS: Apo AI glycation patterns differed between patients with type 2 diabetes with and without CAS, with K96 and K106/107 emerging as prominent disease-associated glycation sites. The Apo AI Glycation Index was independently associated with CAS and coronary artery disease in patients with type 2 diabetes and was inversely associated with HDL-mediated reverse cholesterol transport and lecithin-cholesterol acyltransferase activity. Compared with native apo AI, apo AICL showed reduced key-site glycation, preserved structural stability, enhanced binding affinity to lecithin-cholesterol acyltransferase, and improved HDL-mediated reverse cholesterol transport under glycation conditions. In diabetic mouse models, apo AICL attenuated HDL dysfunction and atherosclerotic lesion formation compared with glycated apo AI. These data support a candidate mechanism in which glycated apo AI enhances RAGE (receptor for advanced glycation end products) interaction and activates ERK1/2 (extracellular signal-regulated kinase 1/2)-NF-κB (nuclear factor κB)/p65 signaling, leading to upregulation of NR2C2 (nuclear receptor subfamily 2 group C member 2). LXRα (liver X receptor α) activation and macrophage NR2C2 deficiency restored cholesterol efflux in glycated apo AI-treated macrophages. CONCLUSIONS: This study provides a comprehensive site-resolved map of apo AI glycation in patients with diabetes and identifies the Apo AI Glycation Index as a glycation signature associated with diabetic CAS and impaired HDL function. Experimental data support a mechanism in which site-specific apo AI glycation contributes to HDL dysfunction and macrophage cholesterol efflux impairment through RAGE-associated NR2C2-LXRα signaling. Glycation-resistant apo AICL preserves HDL function and attenuates atherosclerosis in preclinical models, supporting site-specific apo AI glycation as a mechanistically relevant feature of diabetic atherosclerosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05659043.

Lipoprotein X (LpX) is an abnormal lipoprotein-like particle occurring mainly in cholestasis, lecithin-cholesterol acyltransferase deficiency, post-transplant cholestatic liver dysfunction, hepatic graft-versus-host disease, and selected intravenous lipid emulsion or parenteral nutrition settings. Enrichment in phospholipids and unesterified cholesterol, paucity of cholesteryl esters and triglycerides, and usual absence of apolipoprotein B (apoB) challenge assumptions underlying routine laboratory testing. This review distinguishes analytical interference, in which LpX biases measurement procedures, from interpretative distortion, in which a valid cholesterol result no longer reflects the burden of atherogenic apoB-containing particles. Friedewald, Martin-Hopkins, Sampson, and other calculated LDL-cholesterol (LDL-C) equations cannot identify LpX and may retain its cholesterol in calculated LDL-C; direct LDL-C assays are also method dependent. We propose indicative, rather than diagnostic, screening triggers: in a compatible setting, total cholesterol (TC) ≥500 mg/dL (12.9 mmol/L) may be considered marked and ≥1,000 mg/dL (25.9 mmol/L) extreme; apoB within or slightly above the adult range, together with TC/apoB ≥8 mmol/g or non-HDL-C/apoB ≥7.5 mmol/g, should prompt verification. Confirmation may integrate free cholesterol and cholesteryl ester measurements, configured lipoprotein electrophoresis with filipin staining, apoB depletion, nuclear magnetic resonance, ultracentrifugation with an orthogonal method, or lipidomics. LpX appears less atherogenic than apoB-containing LDL but is not innocuous because xanthomatosis, hyperviscosity, and thrombotic complications may occur, while conventional atherogenic lipoproteins may coexist. ApoB-containing LpY and LpZ may attenuate cholesterol-apoB discordance. A structured LpX-oriented laboratory workflow can reduce misclassification of dyslipidaemia and pseudoelectrolyte disorders and support safer clinical decisions.

BACKGROUND: Hepatocellular carcinoma (HCC), the most common primary liver cancer, exhibits metabolic reprogramming with disrupted cholesterol metabolism as a key feature. Lecithin-cholesterol acyltransferase (LCAT) contributes to HCC development, but its exact on cogenic mechanisms remain unclear. This study aims to investigate the role of LCAT in hepatocarcinogenesis and elucidate its underlying molecular mechanisms in HCC. METHODS: The Cancer Genome Atlas (TCGA), GEPIA, and Kaplan-Meier plotter databases were used to analyze LCAT expression and perform survival analysis and functional enrichment analysis. Clinical paired samples were collected to evaluate LCAT expression and observed changes in cholesterol metabolism levels Liver-specific Lcat knockout mice were constructed to investigate the hepatocarcinogenesis effect of LCAT. Loss-of-function studies were performed to confirm the molecular mechanism of LCAT in HCC. Finally, investigated the correlation between LCAT and immune infiltration. RESULTS: LCAT expression level was down-regulated in HCC patients and low LCAT level was associated with poor prognosis. International Cancer Genome Consortium (ICGC) data reveal dysregulated cholesterol metabolism in HCC, further validated by clinical evidence of metabolic aberrations in patients Besides, we constructed DEN induced HCC model using Alb-Cre; Lcatfl/fl mice and found that liver-specific Lcat knockout promoted cancerogenesis through ERK pathway. Meanwhile, knockdown of LCAT significantly promoted proliferation, migration, and invasion in Huh7 cell. Finally, immune infiltration analysis showed that LCAT was significantly related to immune infiltration, and LCAT expression was significantly associated with more than 10 immune checkpoint markers such as IL12A, VTCN1, BTLA, and TIGIT. CONCLUSION: This study first explored the biological functions of LCAT in HCC based on in vitro and in vivo experiments. Our results indicate that LCAT deficiency correlates with aggressive HCC progression and immunosuppression, suggesting its potential as a prognostic biomarker. Given its role in modulating the HCC microenvironment, LCAT warrants further investigation as a predictive marker for immunotherapy response.

Acquired lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare cause of a marked reduction in high-density lipoprotein cholesterol (HDL-C). We report a 75-year-old Japanese woman with a progressive decline in HDL-C from 64 to <2 mg/dL over five years. Laboratory tests showed a markedly decreased LCAT activity and protein levels with anti-LCAT autoantibodies, whereas a genetic analysis revealed no LCAT mutations. Lipidomic profiling demonstrated free cholesterol accumulation, the loss of HDL subclasses, and TG-rich LDL particles. No underlying autoimmune disease was identified. This case highlights the importance of a lipid subclass analysis and the recognition of acquired LCAT deficiency in patients with a marked HDL-C deficiency.

Familial lecithin-cholesterol acyltransferase deficiency (FLD) is a rare hereditary disorder. In FLD, a clinical triad of corneal opacity, anemia, and proteinuria typically precedes progressive renal dysfunction. Although early renal involvement has been widely described, there are limited reports on the long-term course leading to dialysis initiation, including systemic complications. We present a genetically confirmed case of FLD caused by the Cys74Tyr mutation, which had a clinical course exceeding 10 years with the emergence of multisystem complications. The patient initially showed a transient stabilization of renal function following a fat-restricted and protein-restricted diet and renin-angiotensin system blockade; however, subsequent decline occurred despite continued management. During this deterioration phase, systemic complications emerged, including progressive aortic valve stenosis, complete atrioventricular block, heart failure, and cerebellar infarction, in close temporal association with worsening renal function. Hemodialysis initiation led to rapid resolution of erythropoietin-resistant anemia, which may be attributable to the improvement in the uremic milieu following dialysis initiation. This case offers valuable insights into the late-stage progression of FLD. The observations may help determine the point at which renoprotective and metabolic interventions become less effective. Furthermore, the temporal association between renal deterioration and the development of cardiovascular and neurovascular complications suggests the need for careful clinical surveillance during advanced stages of renal dysfunction.