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Apolipoproteins in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 30311

Special Issue Editors


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Guest Editor
Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain
Interests: biomarkers of cardiovascular disease; cardiovascular risk biomarkers; arteriosclerosis

Special Issue Information

Dear Colleagues, 

We are pleased to support and edit a new Special Issue for the International Journal of Molecular Sciences, entitled “Apolipoproteins in Health and Disease”. Although apolipoproteins were originally recognized as major determinants in lipoprotein metabolism and cardiovascular disease, the multiple apolipoprotein classes and subclasses have emerged as relevant participants in multiple biological processes and pathophysiological pathways involved in diabetes, cancer, obesity, neurodegenerative disorders, and inflammatory and infectious diseases. This Special Issue aims to publish timely and informative findings on molecular aspects of apolipoproteins (including isoforms and posttranslational modifications) and their influence on health and disease risk. Manuscripts of original research and reviews will be welcome.

Dr. Jordi Ordonez-Llanos
Dr. Joan Carles Escolà-Gil
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • apolipoproteins
  • Alzheimer's disease
  • atherosclerosis
  • cancer
  • cholesterol
  • diabetes
  • inflammation
  • obesity
  • lipid metabolism
  • lipoproteins

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Published Papers (11 papers)

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Research

Jump to: Review

18 pages, 3483 KiB  
Article
Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
by Giovanna Revilla, Lara Ruiz-Auladell, Núria Fucui Vallverdú, Paula Santamaría, Antonio Moral, José Ignacio Pérez, Changda Li, Victoria Fuste, Enrique Lerma, Rosa Corcoy, Fabián Pitoia, Joan Carles Escolà-Gil and Eugènia Mato
Int. J. Mol. Sci. 2023, 24(13), 11153; https://doi.org/10.3390/ijms241311153 - 6 Jul 2023
Cited by 1 | Viewed by 2103
Abstract
We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor [...] Read more.
We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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12 pages, 1500 KiB  
Article
Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients
by Carmen Rodríguez-Jiménez, Gema de la Peña, Javier Sanguino, Sara Poyatos-Peláez, Ana Carazo, Pedro L. Martínez-Hernández, Francisco Arrieta, José M. Mostaza, Diego Gómez-Coronado and Sonia Rodríguez-Nóvoa
Int. J. Mol. Sci. 2023, 24(8), 7635; https://doi.org/10.3390/ijms24087635 - 21 Apr 2023
Cited by 2 | Viewed by 1827
Abstract
Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB [...] Read more.
Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB variants in patients with hypercholesterolemia. Index patients (n = 825) with clinically suspected FH were analyzed using next-generation sequencing. In total, 40% of the patients presented a variant in LDLR, APOB, PCSK9 or LDLRAP1, with 12% of the variants in APOB. These variants showed frequencies in the general population lower than 0.5% and were classified as damaging and/or probably damaging by 3 or more predictors of pathogenicity. The variants c.10030A>G;p.(Lys3344Glu) and c.11401T>A;p.(Ser3801Thr) were characterized. The p.(Lys3344Glu) variant co-segregated with high low-density lipoprotein (LDL)-cholesterol in 2 families studied. LDL isolated from apoB p.(Lys3344Glu) heterozygous patients showed reduced ability to compete with fluorescently-labelled LDL for cellular binding and uptake compared with control LDL and was markedly deficient in supporting U937 cell proliferation. LDL that was carrying apoB p.(Ser3801Thr) was not defective in competing with control LDL for cellular binding and uptake. We conclude that the apoB p.(Lys3344Glu) variant is defective in the interaction with the LDL receptor and is causative of FH, whereas the apoB p.(Ser3801Thr) variant is benign. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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19 pages, 2671 KiB  
Article
Increased BAT Thermogenesis in Male Mouse Apolipoprotein A4 Transgenic Mice
by Zachary LaRussa, Hsuan-Chih N. Kuo, Kathryn West, Zhijun Shen, Kevin Wisniewski, Patrick Tso, Karen T. Coschigano and Chunmin C. Lo
Int. J. Mol. Sci. 2023, 24(4), 4231; https://doi.org/10.3390/ijms24044231 - 20 Feb 2023
Cited by 1 | Viewed by 1833
Abstract
Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) [...] Read more.
Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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12 pages, 3309 KiB  
Article
The Association between Apolipoprotein B, Cardiovascular Risk Factors and Subclinical Atherosclerosis—Findings from the SEPHAR National Registry on Hypertension in Romania
by Maria Dorobanțu, Vasile-Bogdan Halațiu, Oana Gheorghe-Fronea, Cornelia-Gabriela Bala, Horațiu Moldovan, Raluca Irinel-Parepa, Ioana-Patricia Rodean, Imre Benedek and Theodora Benedek
Int. J. Mol. Sci. 2023, 24(3), 2813; https://doi.org/10.3390/ijms24032813 - 1 Feb 2023
Cited by 5 | Viewed by 4142
Abstract
The present study aimed to investigate the association between apolipoprotein B (Apo B) and classical features associated with clinical or subclinical atherosclerosis. A total of 811 adult patients from the general Romanian population, included in the national SEPHAR registry on hypertension, were divided [...] Read more.
The present study aimed to investigate the association between apolipoprotein B (Apo B) and classical features associated with clinical or subclinical atherosclerosis. A total of 811 adult patients from the general Romanian population, included in the national SEPHAR registry on hypertension, were divided into two groups based on Apo B value (low versus high Apo B with a cut-off established at 130 mg/dL) and subsequently into four subgroups according to the cut-offs recommended by the 2021 ESC Guidelines on Cardiovascular Disease Prevention. In all patients, lipid profile, uric acid, full blood count and presence of significant carotid plaques were assessed. Apo B levels were positively correlated with proatherogenic lipids (total cholesterol, triglycerides and LDL-cholesterol, p < 0.0001) and negatively correlated with HDL cholesterol (all p < 0.05). In comparison with patients with low Apo B levels, those with elevated Apo B levels more frequently presented significant carotid plaques (17% vs. 19% vs. 28% vs. 46%, p < 0.0001). Univariate regression analysis identified a strong association between the level of uric acid and increased value of Apo B in the four subgroups (uric acid 4.8 +/− 1.3 vs. 5 +/− 1.6 vs. 5.1 +/− 1.5 vs. 5.8 +/− 1.6, r = 0.2, p < 0.0001). The results of this nationwide registry on hypertension in Romania indicate that high Apo B may be considered as a risk factor for CVD, promoting atherosclerosis and associated with increased expression of classical markers of clinical or subclinical CVD. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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17 pages, 1139 KiB  
Article
Apolipoproteins—New Biomarkers of Overweight and Obesity among Childhood Acute Lymphoblastic Leukemia Survivors?
by Klaudia Sztolsztener, Hubert Żywno, Katarzyna Hodun, Katarzyna Konończuk, Katarzyna Muszyńska-Rosłan and Eryk Latoch
Int. J. Mol. Sci. 2022, 23(18), 10634; https://doi.org/10.3390/ijms231810634 - 13 Sep 2022
Cited by 3 | Viewed by 1751
Abstract
Patients suffering from childhood acute lymphoblastic leukemia (ALL) are at risk of late adverse treatment-related effects. The examination of targeted biomarkers could be used to improve the diagnosis and prediction of life-threatening ALL sequelae. The purpose of this cross-sectional study was to search [...] Read more.
Patients suffering from childhood acute lymphoblastic leukemia (ALL) are at risk of late adverse treatment-related effects. The examination of targeted biomarkers could be used to improve the diagnosis and prediction of life-threatening ALL sequelae. The purpose of this cross-sectional study was to search for treatment-related alterations in apolipoprotein (Apo) levels as potential markers of the occurrence of obesity in subjects treated for ALL, and to assess the relationships between weight, gender, anticancer treatment, and Apo concentrations. Fifty-eight ALL survivors were included in the study. The mean time of follow-up after treatment cessation was 5.41 ± 4.29 years. Serum levels of apolipoproteins were measured using a multiplex assay kit. Among ALL survivors, we observed a significant correlation of Apo-C1, Apo-C3, Apo-H, and Apo-J levels, depending on body mass index (BMI). Marked differences were observed in the area under the curve of Apo-A1, Apo-A2, Apo-C1, Apo-D. In our study, patients with a history of childhood ALL developed alterations in their Apo profile. Furthermore, this is the first study revealing that some apolipoproteins may act as valuable biomarkers useful in the prognosis of metabolic imbalance. We believe that this paper, at least partially, will highlight the importance of long-term prognosis of metabolic complications associated with the anticancer chemotherapy used to treat hematological malignancies in children. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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12 pages, 290 KiB  
Article
Association between APOE Genotype with Body Composition and Cardiovascular Disease Risk Markers Is Modulated by BMI in Healthy Adults: Findings from the BODYCON Study
by Ezgi Ozen, Rada G. Mihaylova, Natalie J. Lord, Julie A. Lovegrove and Kim G. Jackson
Int. J. Mol. Sci. 2022, 23(17), 9766; https://doi.org/10.3390/ijms23179766 - 29 Aug 2022
Cited by 6 | Viewed by 2329
Abstract
Body mass index (BMI) has been suggested to play an important role in the relationship between the APOLIPOPROTEIN (APO)E genotype and cardiovascular disease (CVD) risk. Using data from the BODYCON cross-sectional study (n = 360 adults) we assessed the association between body [...] Read more.
Body mass index (BMI) has been suggested to play an important role in the relationship between the APOLIPOPROTEIN (APO)E genotype and cardiovascular disease (CVD) risk. Using data from the BODYCON cross-sectional study (n = 360 adults) we assessed the association between body composition and CVD risk markers according to APOE genotype, with examination of the role of BMI. In this study cohort, the APOE2/E3 group had lower fasting blood lipids than APOE4 carriers and APOE3/E3 group (p ≤ 0.01). After stratifying the group according to BMI, APOE4 carriers in the normal BMI subgroup had a higher lean mass compared with the APOE3/E3 group (p = 0.02) whereas in the overweight/obese subgroup, the android to gynoid percentage fat ratio was lower in APOE4 carriers than APOE3/E3 group (p = 0.04). Fasting lipid concentrations were only different between the APOE2/E3 and other genotype groups within the normal weight BMI subgroup (p ≤ 0.04). This finding was associated with a lower dietary fibre and a higher trans-fat intake compared with APOE4 carriers, and a lower carbohydrate intake relative to the APOE3/E3 group. Our results confirm previous reports that BMI modulates the effect of APOE on CVD risk markers and suggest novel interactions on body composition, with diet a potential modulator of this relationship. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
17 pages, 2560 KiB  
Article
Decoding Functional High-Density Lipoprotein Particle Surfaceome Interactions
by Kathrin Frey, Sandra Goetze, Lucia Rohrer, Arnold von Eckardstein and Bernd Wollscheid
Int. J. Mol. Sci. 2022, 23(16), 9506; https://doi.org/10.3390/ijms23169506 - 22 Aug 2022
Cited by 3 | Viewed by 2443
Abstract
High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol transport (RCT) and several cytoprotective activities. Despite its relevance for human health, many aspects of HDL-mediated lipid trafficking and cellular signaling remain elusive at the molecular level. During HDL’s journey throughout [...] Read more.
High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol transport (RCT) and several cytoprotective activities. Despite its relevance for human health, many aspects of HDL-mediated lipid trafficking and cellular signaling remain elusive at the molecular level. During HDL’s journey throughout the body, its functions are mediated through interactions with cell surface receptors on different cell types. To characterize and better understand the functional interplay between HDL particles and tissue, we analyzed the surfaceome-residing receptor neighborhoods with which HDL potentially interacts. We applied a combination of chemoproteomic technologies including automated cell surface capturing (auto-CSC) and HATRIC-based ligand–receptor capturing (HATRIC-LRC) on four different cellular model systems mimicking tissues relevant for RCT. The surfaceome analysis of EA.hy926, HEPG2, foam cells, and human aortic endothelial cells (HAECs) revealed the main currently known HDL receptor scavenger receptor B1 (SCRB1), as well as 155 shared cell surface receptors representing potential HDL interaction candidates. Since vascular endothelial growth factor A (VEGF-A) was recently found as a regulatory factor of transendothelial transport of HDL, we next analyzed the VEGF-modulated surfaceome of HAEC using the auto-CSC technology. VEGF-A treatment led to the remodeling of the surfaceome of HAEC cells, including the previously reported higher surfaceome abundance of SCRB1. In total, 165 additional receptors were found on HAEC upon VEGF-A treatment representing SCRB1 co-regulated receptors potentially involved in HDL function. Using the HATRIC-LRC technology on human endothelial cells, we specifically aimed for the identification of other bona fide (co-)receptors of HDL beyond SCRB1. HATRIC-LRC enabled, next to SCRB1, the identification of the receptor tyrosine-protein kinase Mer (MERTK). Through RNA interference, we revealed its contribution to endothelial HDL binding and uptake. Furthermore, subsequent proximity ligation assays (PLAs) demonstrated the spatial vicinity of MERTK and SCRB1 on the endothelial cell surface. The data shown provide direct evidence for a complex and dynamic HDL receptome and that receptor nanoscale organization may influence binding and uptake of HDL. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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11 pages, 2451 KiB  
Article
On the Aggregation of Apolipoprotein A-I
by Rebecca Frankel, Emma Sparr and Sara Linse
Int. J. Mol. Sci. 2022, 23(15), 8780; https://doi.org/10.3390/ijms23158780 - 7 Aug 2022
Cited by 3 | Viewed by 1752
Abstract
In vivo, apolipoprotein A-I (ApoA-I) is commonly found together with lipids in so-called lipoprotein particles. The protein has also been associated with several diseases—such as atherosclerosis and amyloidosis—where insoluble aggregates containing ApoA-I are deposited in various organs or arteries. The deposited ApoA-I has [...] Read more.
In vivo, apolipoprotein A-I (ApoA-I) is commonly found together with lipids in so-called lipoprotein particles. The protein has also been associated with several diseases—such as atherosclerosis and amyloidosis—where insoluble aggregates containing ApoA-I are deposited in various organs or arteries. The deposited ApoA-I has been found in the form of amyloid fibrils, suggesting that amyloid formation may be involved in the development of these diseases. In the present study we investigated ApoA-I aggregation into amyloid fibrils and other aggregate morphologies. We studied the aggregation of wildtype ApoA-I as well as a disease-associated mutant, ApoA-I K107Δ, under different solution conditions. The aggregation was followed using thioflavin T fluorescence intensity. For selected samples the aggregates formed were characterized in terms of size, secondary structure content, and morphology using circular dichroism spectroscopy, dynamic light scattering, atomic force microscopy and cryo transmission electron microscopy. We find that ApoA-I may form globular protein-only condensates, in which the α-helical conformation of the protein is retained. The protein in its unmodified form appears resistant to amyloid formation; however, the conversion into amyloid fibrils rich in β-sheet is facilitated by oxidation or mutation. In particular, the K107Δ mutant shows higher amyloid formation propensity, and the end state appears to be a co-existence of β-sheet rich amyloid fibrils and α-helix-rich condensates. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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Review

Jump to: Research

23 pages, 1309 KiB  
Review
Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases
by Jeyashree Alagarsamy, Anja Jaeschke and David Y. Hui
Int. J. Mol. Sci. 2022, 23(17), 9892; https://doi.org/10.3390/ijms23179892 - 31 Aug 2022
Cited by 19 | Viewed by 4115
Abstract
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three [...] Read more.
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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14 pages, 1042 KiB  
Review
Cholesteryl Ester Transfer Protein Inhibition Reduces Major Adverse Cardiovascular Events by Lowering Apolipoprotein B Levels
by Adam J. Nelson, Allan D. Sniderman, Marc Ditmarsch, Mary R. Dicklin, Stephen J. Nicholls, Michael H. Davidson and John J. P. Kastelein
Int. J. Mol. Sci. 2022, 23(16), 9417; https://doi.org/10.3390/ijms23169417 - 20 Aug 2022
Cited by 24 | Viewed by 3081
Abstract
Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought [...] Read more.
Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought to lower the risk of atherosclerotic cardiovascular disease (ASCVD). More recently, the focus changed and the use of pharmacologic CETP inhibitors to reduce low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apoB concentrations became supported by several lines of evidence from animal models, observational investigations, randomized controlled trials and Mendelian randomization studies. Furthermore, a cardiovascular outcome trial of anacetrapib demonstrated that CETP inhibition significantly reduced the risk of major coronary events in patients with ASCVD in a manner directly proportional to the substantial reduction in LDL-C and apoB. These data have dramatically shifted the attention on CETP away from raising HDL-C instead to lowering apoB-containing lipoproteins, which is relevant since the newest CETP inhibitor, obicetrapib, reduces LDL-C by up to 51% and apoB by up to 30% when taken in combination with a high-intensity statin. An ongoing cardiovascular outcome trial of obicetrapib in patients with ASCVD is expected to provide further evidence of the ability of CETP inhibitors to reduce major adverse cardiovascular events by lowering apoB. The purpose of the present review is to provide an up-to-date understanding of CETP inhibition and its relationship to ASCVD risk reduction. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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20 pages, 1833 KiB  
Review
HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis
by Carla Borràs, Aina Mercer, Sònia Sirisi, Daniel Alcolea, Joan Carles Escolà-Gil, Francisco Blanco-Vaca and Mireia Tondo
Int. J. Mol. Sci. 2022, 23(16), 9356; https://doi.org/10.3390/ijms23169356 - 19 Aug 2022
Cited by 11 | Viewed by 3439
Abstract
The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta [...] Read more.
The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis. Full article
(This article belongs to the Special Issue Apolipoproteins in Health and Disease)
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