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Neurobiology of Disease Dec 2014ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential... (Review)
Review
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of high density lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer's disease (AD). A series of reports have revealed a significant impact of ABCA1 on Aβ deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.
Topics: ATP Binding Cassette Transporter 1; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Atherosclerosis; Brain; Disease Models, Animal; Humans; Mice; Risk Factors; Tangier Disease
PubMed: 24844148
DOI: 10.1016/j.nbd.2014.05.007 -
The FEBS Journal Sep 2011The ATP-binding cassette protein A1 (ABCA1) mediates the secretion of cellular-free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein A-I, to... (Review)
Review
The ATP-binding cassette protein A1 (ABCA1) mediates the secretion of cellular-free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein A-I, to form high-density lipoprotein. Because ABCA1 is a key factor in cholesterol homeostasis, elaborate transcriptional and post-transcriptional regulations of ABCA1 have evolved to maintain cholesterol homeostasis. Recent studies suggest that ABCA1 moves lipids not only between membranes but also within membranes to organize and reorganize membrane meso-domains to modulate cell proliferation and immunity.
Topics: ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Animals; Apolipoproteins; Cholesterol; Gene Expression Regulation; Homeostasis; Humans; Membrane Microdomains; Mutation; Protein Processing, Post-Translational; Protein Transport; Tangier Disease
PubMed: 21554545
DOI: 10.1111/j.1742-4658.2011.08170.x -
Current Opinion in Lipidology Apr 2020To review recent lecithin:cholesterol acyltransferas (LCAT)-based therapeutic approaches for atherosclerosis, acute coronary syndrome, and LCAT deficiency disorders.
PURPOSE OF REVIEW
To review recent lecithin:cholesterol acyltransferas (LCAT)-based therapeutic approaches for atherosclerosis, acute coronary syndrome, and LCAT deficiency disorders.
RECENT FINDINGS
A wide variety of approaches to using LCAT as a novel therapeutic target have been proposed. Enzyme replacement therapy with recombinant human LCAT is the most clinically advanced therapy for atherosclerosis and familial LCAT deficiency (FLD), with Phase I and Phase 2A clinical trials recently completed. Liver-directed LCAT gene therapy and engineered cell therapies are also another promising approach. Peptide and small molecule activators have shown efficacy in early-stage preclinical studies. Finally, lifestyle modifications, such as fat-restricted diets, cessation of cigarette smoking, and a diet rich in antioxidants may potentially suppress lipoprotein abnormalities in FLD patients and help preserve LCAT activity and renal function but have not been adequately tested.
SUMMARY
Preclinical and early-stage clinical trials demonstrate the promise of novel LCAT therapies as HDL-raising agents that may be used to treat not only FLD but potentially also atherosclerosis and other disorders with low or dysfunctional HDL.
Topics: Animals; Enzyme Replacement Therapy; Humans; Lecithin Cholesterol Acyltransferase Deficiency; Phosphatidylcholine-Sterol O-Acyltransferase; Sterol O-Acyltransferase
PubMed: 32073411
DOI: 10.1097/MOL.0000000000000673 -
European Cytokine Network Dec 2007Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta],...
Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta], interleukin-6 [IL-6] and interleukin-8 [IL-8]), and causes metabolic alterations in the early, post-traumatic state, either in the brain or/and the systemic circulation. The metabolic changes involve carbohydrates, proteins and lipids. We focused on the serum lipid profile, the impact of trauma on lipoproteins, and their subsequent effects, on inflammation. We investigated the role of cytokines and serum lipids, in patient outcome, reviewing 30-day mortality and the Glasgow Coma Scale (GCS). A total of 75 patients with severe or moderate TBI (GCS
Topics: Adolescent; Adult; Aged; Brain Injuries; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Glasgow Coma Scale; Humans; Hypolipoproteinemias; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged
PubMed: 17993453
DOI: 10.1684/ecn.2007.0112 -
Clinica E Investigacion En... 2023Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic...
Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband's clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene.
Topics: Humans; Female; Proprotein Convertase 9; Hypobetalipoproteinemias; Hypolipoproteinemias; Cholesterol, LDL; Apolipoproteins B
PubMed: 37302939
DOI: 10.1016/j.arteri.2023.05.003 -
Disease Models & Mechanisms Jan 2016Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life... (Review)
Review
Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.
Topics: Abetalipoproteinemia; Animals; Chylomicrons; Diarrhea; Diarrhea, Infantile; Enterocytes; Facies; Fetal Growth Retardation; Hair Diseases; Heterozygote; Humans; Hypobetalipoproteinemias; Lipids; Mice; Mice, Knockout; Microvilli; Models, Animal; Mutation; Protein Transport; Registries; Stem Cells
PubMed: 26747865
DOI: 10.1242/dmm.022269 -
Journal of Atherosclerosis and... Jan 2020
Topics: ATP Binding Cassette Transporter 1; Animals; Cholesterol, HDL; Female; Fertility; Lecithin Cholesterol Acyltransferase Deficiency; Male; Mice; Probucol; Scavenger Receptors, Class B
PubMed: 31484853
DOI: 10.5551/jat.ED115 -
Journal of Lipid Research Mar 2022Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe... (Review)
Review
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.
Topics: Humans; Biomarkers; Heterozygote; Lecithin Cholesterol Acyltransferase Deficiency; Mutation; Phosphatidylcholine-Sterol O-Acyltransferase
PubMed: 35065092
DOI: 10.1016/j.jlr.2022.100169 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Oct 2010Hypocholesterolemia is characterized by serum total cholesterol that is lower than the 5th percentile for age and sex, or the cut-off value which predicts the adverse... (Review)
Review
Hypocholesterolemia is characterized by serum total cholesterol that is lower than the 5th percentile for age and sex, or the cut-off value which predicts the adverse prognosis by epidemiological study. Unlike hypercholesterolemia, physicians pay less attention to the morbidity, causes and consequences of hypocholesterolemia in clinical practice. In fact, hypocholesterolemia is a common dislipidemia, and mainly results from secondary factors. The causes of primary hypocholesterolemia are some disorders owing to genetic mutation in the pathway of cholesterol absorption, biosynthesis or metabolism, including abetalipoproteinemia, hypobetalipoproteinemia, Tangier disease, chylomicron retention disease and inherited disorders of cholesterol biosynthesis. The causes of secondary hypocholesterolemia comprise anemia, hyperthyroidism, malignancy, live disease, critical illness, serious stress, malabsorption or malnutrition, acute or chronic infection, chronic inflammation, and use of some drugs. In addition, what's more important is that hypocholesterolemia can result in some adverse events, such as increased mortality, intracerebral hemorrhage, cancer, infection, adrenal failure, suicide and mental disorder. Therefore, with the practice of intensive lipid-lowering treatment and the tendency to the increased indications of statins, it's high time that physicians attached more importance to hypocholesterolemia.
Topics: Animals; Dyslipidemias; Humans; Hypolipoproteinemias
PubMed: 20957025
DOI: No ID Found -
Anales de Pediatria (Barcelona, Spain :... Jun 2003We present the case of a 5-month-old girl, with consanguineous parents, who was born at 28 weeks of gestation and who showed intermittent signs of abdominal distension...
We present the case of a 5-month-old girl, with consanguineous parents, who was born at 28 weeks of gestation and who showed intermittent signs of abdominal distension accompanied by increased regurgitation and vomiting after food intake. Significant biochemical alterations (reduced levels of triglicerides, cholesterol, and vitamin A and absence of apolipoprotein B and vitamin E) led to the diagnosis of homozygous hypobetalipoproteinemia, which was subsequently confirmed by genetic studies.
Topics: Female; Humans; Hypobetalipoproteinemias; Infant; Male; Vitamin A Deficiency; Vitamin E Deficiency
PubMed: 12781120
DOI: 10.1016/s1695-4033(03)78130-2