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Lipoprotein Metabolism in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 12747

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Guest Editor
INSERM UMR_S Acute and Chronic Cardiovascular Failure, DCAC, Faculty of Medicine, University of Lorraine, 54505 Vandoeuvre-lès-Nancy, France
Interests: lipid homeostasis; lipoprotein receptors; dyslipidemias; obesity; brain aging; apolipoprotein E; Alzheimer’s disease; inflammation; atherosclerosis
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Special Issue Information

Dear Colleagues,

Lipid homeostasis represents the coordination and regulation of numerous complex processes that work to ensure a balance between lipid influx and efflux in order to maintain the optimal lipid status required for normal cell function. As the vehicles that provide the means to deliver and transport both cholesterol and fatty acids as energy substrates to different tissues, lipoproteins are key in maintaining this balance. Lipoprotein metabolism relies on a number of enzymes, transfer proteins, apolipoproteins, and receptors to ensure the delivery and transport of lipids to different tissues. The imbalance or deregulation of lipid homeostasis can manifest as different forms of dyslipidemias, which can contribute or serve as markers of the physiopathology of a number of diseases, including cardiovascular and metabolic diseases, as well as neurodegenerative diseases such as Alzheimer’s disease. Despite the advances in the field of lipoprotein metabolism in the past few decades, the causal relationship between lipoproteins and these different pathologies remains under active investigation.

The aim of this Special Issue is to highlight new discoveries and present up-to-date reviews in order to further enrich our understanding of the role of lipoprotein metabolism in different physiopathologies ranging from cardiovascular and metabolic to neurodegenerative diseases, and that identify innovative strategies or therapeutics for the prevention or treatment of these pathologies.

Original articles or focused reviews addressing these topics will be considered for publication.

Dr. Frances T. Yen
Guest Editor

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Keywords

  • lipoproteins
  • lipoprotein receptors
  • lipid homeostasis
  • cholesterol
  • triglycerides
  • fatty acids
  • postprandial lipemia
  • inflammation
  • atherosclerosis
  • obesity
  • diabetes
  • cardiovascular disease
  • metabolic syndrome
  • Alzheimer’s disease
  • neurodegenerative disease

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Published Papers (9 papers)

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Research

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17 pages, 2817 KiB  
Article
Increasing the Survival of a Neuronal Model of Alzheimer’s Disease Using Docosahexaenoic Acid, Restoring Endolysosomal Functioning by Modifying the Interactions between the Membrane Proteins C99 and Rab5
by Maxime Vigier, Magalie Uriot, Fathia Djelti-Delbarba, Thomas Claudepierre, Aseel El Hajj, Frances T. Yen, Thierry Oster and Catherine Malaplate
Int. J. Mol. Sci. 2024, 25(13), 6816; https://doi.org/10.3390/ijms25136816 - 21 Jun 2024
Viewed by 162
Abstract
Docosahexaenoic acid (DHA, C22:6 ω3) may be involved in various neuroprotective mechanisms that could prevent Alzheimer’s disease (AD). Its influence has still been little explored regarding the dysfunction of the endolysosomal pathway, known as an early key event in the physiopathological continuum triggering [...] Read more.
Docosahexaenoic acid (DHA, C22:6 ω3) may be involved in various neuroprotective mechanisms that could prevent Alzheimer’s disease (AD). Its influence has still been little explored regarding the dysfunction of the endolysosomal pathway, known as an early key event in the physiopathological continuum triggering AD. This dysfunction could result from the accumulation of degradation products of the precursor protein of AD, in particular the C99 fragment, capable of interacting with endosomal proteins and thus contributing to altering this pathway from the early stages of AD. This study aims to evaluate whether neuroprotection mediated by DHA can also preserve the endolysosomal function. AD-typical endolysosomal abnormalities were recorded in differentiated human SH-SY5Y neuroblastoma cells expressing the Swedish form of human amyloid precursor protein. This altered phenotype included endosome enlargement, the reduced secretion of exosomes, and a higher level of apoptosis, which confirmed the relevance of the cellular model chosen for studying the associated deleterious mechanisms. Second, neuroprotection mediated by DHA was associated with a reduced interaction of C99 with the Rab5 GTPase, lower endosome size, restored exosome production, and reduced neuronal apoptosis. Our data reveal that DHA may influence protein localization and interactions in the neuronal membrane environment, thereby correcting the dysfunction of endocytosis and vesicular trafficking associated with AD. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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11 pages, 1264 KiB  
Communication
Total Outflow of High-Density Lipoprotein–Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction
by María Luna-Luna, Martha Franco, Elizabeth Carreón-Torres, Nonanzit Pérez-Hernández, José Manuel Fragoso, Rocío Bautista-Pérez and Óscar Pérez-Méndez
Int. J. Mol. Sci. 2023, 24(23), 17090; https://doi.org/10.3390/ijms242317090 - 4 Dec 2023
Viewed by 722
Abstract
(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein [...] Read more.
(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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15 pages, 1321 KiB  
Article
Associations between Endothelial Lipase and Apolipoprotein B-Containing Lipoproteins Differ in Healthy Volunteers and Metabolic Syndrome Patients
by Iva Klobučar, Lucija Klobučar, Margarete Lechleitner, Matias Trbušić, Gudrun Pregartner, Andrea Berghold, Hansjörg Habisch, Tobias Madl, Saša Frank and Vesna Degoricija
Int. J. Mol. Sci. 2023, 24(13), 10681; https://doi.org/10.3390/ijms241310681 - 26 Jun 2023
Cited by 2 | Viewed by 857
Abstract
The association between serum levels of endothelial lipase (EL) and the serum levels and composition of apolipoprotein B (apoB)-containing lipoproteins in healthy subjects and patients with metabolic syndrome (MS) remained unexplored. Therefore, in the present study, we determined the serum levels and lipid [...] Read more.
The association between serum levels of endothelial lipase (EL) and the serum levels and composition of apolipoprotein B (apoB)-containing lipoproteins in healthy subjects and patients with metabolic syndrome (MS) remained unexplored. Therefore, in the present study, we determined the serum levels and lipid content of apoB-containing lipoproteins using nuclear magnetic resonance (NMR) spectroscopy and examined their association with EL serum levels in healthy volunteers (HVs) and MS patients. EL was significantly negatively correlated with the serum levels of cholesterol in large very low-density lipoprotein (VLDL) particles, as well as with total-cholesterol-, free-cholesterol-, triglyceride-, and phospholipid-contents of VLDL and intermediate-density lipoprotein particles in MS patients but not in HVs. In contrast, EL serum levels were significantly positively correlated with the serum levels of apoB, triglycerides, and phospholipids in large low-density lipoprotein particles in HVs but not in MS patients. EL serum levels as well as the serum levels and lipid content of the majority of apoB-containing lipoprotein subclasses were markedly different in MS patients compared with HVs. We conclude that EL serum levels are associated with the serum levels and lipid content of apoB-containing lipoproteins and that these associations are markedly affected by MS. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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21 pages, 2885 KiB  
Article
Lipid-Sensing Receptor FFAR4 Modulates Pulmonary Epithelial Homeostasis following Immunogenic Exposures Independently of the FFAR4 Ligand Docosahexaenoic Acid (DHA)
by Stefanie N. Sveiven, Kyle Anesko, Joshua Morgan, Meera G. Nair and Tara M. Nordgren
Int. J. Mol. Sci. 2023, 24(8), 7072; https://doi.org/10.3390/ijms24087072 - 11 Apr 2023
Cited by 2 | Viewed by 1549
Abstract
The role of pulmonary free fatty acid receptor 4 (FFAR4) is not fully elucidated and we aimed to clarify the impact of FFAR4 on the pulmonary immune response and return to homeostasis. We employed a known high-risk human pulmonary immunogenic exposure to extracts [...] Read more.
The role of pulmonary free fatty acid receptor 4 (FFAR4) is not fully elucidated and we aimed to clarify the impact of FFAR4 on the pulmonary immune response and return to homeostasis. We employed a known high-risk human pulmonary immunogenic exposure to extracts of dust from swine confinement facilities (DE). WT and Ffar4-null mice were repetitively exposed to DE via intranasal instillation and supplemented with docosahexaenoic acid (DHA) by oral gavage. We sought to understand if previous findings of DHA-mediated attenuation of the DE-induced inflammatory response are FFAR4-dependent. We identified that DHA mediates anti-inflammatory effects independent of FFAR4 expression, and that DE-exposed mice lacking FFAR4 had reduced immune cells in the airways, epithelial dysplasia, and impaired pulmonary barrier integrity. Analysis of transcripts using an immunology gene expression panel revealed a role for FFAR4 in lungs related to innate immune initiation of inflammation, cytoprotection, and immune cell migration. Ultimately, the presence of FFAR4 in the lung may regulate cell survival and repair following immune injury, suggestive of potential therapeutic directions for pulmonary disease. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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13 pages, 955 KiB  
Article
HDL Function and Size in Patients with On-Target LDL Plasma Levels and a First-Onset ACS
by Alberto Cordero, Natàlia Muñoz-García, Teresa Padró, Gemma Vilahur, Vicente Bertomeu-González, David Escribano, Emilio Flores, Pilar Zuazola and Lina Badimon
Int. J. Mol. Sci. 2023, 24(6), 5391; https://doi.org/10.3390/ijms24065391 - 11 Mar 2023
Viewed by 1927
Abstract
Patients admitted for acute coronary syndrome (ACS) usually have high cardiovascular risk scores with low levels of high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels. Here, we investigated the role of lipoprotein functionality as well as particle number and size [...] Read more.
Patients admitted for acute coronary syndrome (ACS) usually have high cardiovascular risk scores with low levels of high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels. Here, we investigated the role of lipoprotein functionality as well as particle number and size in patients with a first-onset ACS with on-target LDL-C levels. Ninety-seven patients with chest pain and first-onset ACS with LDL-C levels of 100 ± 4 mg/dL and non-HDL-C levels of 128 ± 4.0 mg/dL were included in the study. Patients were categorized as ACS and non-ACS after all diagnostic tests were performed (electrocardiogram, echocardiogram, troponin levels and angiography) on admission. HDL-C and LDL-C functionality and particle number/size by nuclear magnetic resonance (NMR) were blindly investigated. A group of matched healthy volunteers (n = 31) was included as a reference for these novel laboratory variables. LDL susceptibility to oxidation was higher and HDL-antioxidant capacity lower in the ACS patients than in the non-ACS individuals. ACS patients had lower HDL-C and Apolipoprotein A-I levels than non-ACS patients despite the same prevalence of classical cardiovascular risk factors. Cholesterol efflux potential was impaired only in the ACS patients. ACS-STEMI (Acute Coronary Syndrome—ST-segment-elevation myocardial infarction) patients, had a larger HDL particle diameter than non-ACS individuals (8.4 ± 0.02 vs. 8.3 ± 0.02 and, ANOVA test, p = 0.004). In conclusion, patients admitted for chest pain with a first-onset ACS and on-target lipid levels had impaired lipoprotein functionality and NMR measured larger HDL particles. This study shows the relevance of HDL functionality rather than HDL-C concentration in ACS patients. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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16 pages, 5179 KiB  
Article
Plasma Apolipoprotein Concentrations Are Highly Altered in Severe Intensive Care Unit COVID-19 Patients: Preliminary Results from the LIPICOR Cohort Study
by Floran Begue, Kévin Chemello, Bryan Veeren, Brice Lortat-Jacob, Alexy Tran-Dinh, Nathalie Zappella, Aurelie Snauwaert, Tiphaine Robert, Philippe Rondeau, Marie Lagrange-Xelot, Philippe Montravers, David Couret, Sébastien Tanaka and Olivier Meilhac
Int. J. Mol. Sci. 2023, 24(5), 4605; https://doi.org/10.3390/ijms24054605 - 27 Feb 2023
Cited by 7 | Viewed by 1389
Abstract
SARS-CoV-2 infection goes beyond acute pneumonia, as it also impacts lipid metabolism. Decreased HDL-C and LDL-C levels have been reported in patients with COVID-19. The lipid profile is a less robust biochemical marker than apolipoproteins, components of lipoproteins. However, the association of apolipoprotein [...] Read more.
SARS-CoV-2 infection goes beyond acute pneumonia, as it also impacts lipid metabolism. Decreased HDL-C and LDL-C levels have been reported in patients with COVID-19. The lipid profile is a less robust biochemical marker than apolipoproteins, components of lipoproteins. However, the association of apolipoprotein levels during COVID-19 is not well described and understood. The objective of our study is to measure plasma levels of 14 apolipoproteins in patients with COVID-19 and to evaluate the relationships between apolipoprotein levels, severity factors and patient outcomes. From November to March 2021, 44 patients were recruited on admission to the intensive care unit because of COVID-19. Fourteen apolipoproteins and LCAT were measured by LC-MS/MS in plasma of 44 COVID-19 patients on admission to the ICU and 44 healthy control subjects. Absolute apolipoprotein concentrations were compared between COVID-19 patients and controls. Plasma apolipoproteins (Apo) A (I, II, IV), C(I, II), D, H, J and M and LCAT were lower in COVID-19 patients, whereas Apo E was higher. COVID-19 severity factors such as PaO2/FiO2 ratio, SO-FA score and CRP were correlated with certain apolipoproteins. Lower Apo B100 and LCAT levels were observed in non-survivors of COVID-19 versus survivors. To conclude, in this study, lipid and apolipoprotein profiles are altered in COVID-19 patients. Low Apo B100 and LCAT levels may be predictive of non-survival in COVID-19 patients. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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Review

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14 pages, 882 KiB  
Review
Assessment of Apolipoprotein(a) Isoform Size Using Phenotypic and Genotypic Methods
by Federica Fogacci, Valentina Di Micoli, Ashot Avagimyan, Marina Giovannini, Egidio Imbalzano and Arrigo F. G. Cicero
Int. J. Mol. Sci. 2023, 24(18), 13886; https://doi.org/10.3390/ijms241813886 - 9 Sep 2023
Cited by 6 | Viewed by 1121
Abstract
Apolipoprotein(a) (apo(a)) is the protein component that defines lipoprotein(a) (Lp(a)) particles and is encoded by the LPA gene. The apo(a) is extremely heterogeneous in size due to the copy number variations in the kringle-IV type 2 (KIV2) domains. In this review, we aim [...] Read more.
Apolipoprotein(a) (apo(a)) is the protein component that defines lipoprotein(a) (Lp(a)) particles and is encoded by the LPA gene. The apo(a) is extremely heterogeneous in size due to the copy number variations in the kringle-IV type 2 (KIV2) domains. In this review, we aim to discuss the role of genetics in establishing Lp(a) as a risk factor for coronary heart disease (CHD) by examining a series of molecular biology techniques aimed at identifying the best strategy for a possible application in clinical research and practice, according to the current gold standard. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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22 pages, 2420 KiB  
Review
Lipoprotein(a): Just an Innocent Bystander in Arterial Hypertension?
by Gabriele Brosolo, Andrea Da Porto, Stefano Marcante, Alessandro Picci, Filippo Capilupi, Patrizio Capilupi, Luca Bulfone, Antonio Vacca, Nicole Bertin, Cinzia Vivarelli, Jacopo Comand, Cristiana Catena and Leonardo A. Sechi
Int. J. Mol. Sci. 2023, 24(17), 13363; https://doi.org/10.3390/ijms241713363 - 29 Aug 2023
Cited by 3 | Viewed by 1862
Abstract
Elevated plasma lipoprotein(a) [Lp(a)] is a relatively common and highly heritable trait conferring individuals time-dependent risk of developing atherosclerotic cardiovascular disease (CVD). Following its first description, Lp(a) triggered enormous scientific interest in the late 1980s, subsequently dampened in the mid-1990s by controversial findings [...] Read more.
Elevated plasma lipoprotein(a) [Lp(a)] is a relatively common and highly heritable trait conferring individuals time-dependent risk of developing atherosclerotic cardiovascular disease (CVD). Following its first description, Lp(a) triggered enormous scientific interest in the late 1980s, subsequently dampened in the mid-1990s by controversial findings of some prospective studies. It was only in the last decade that a large body of evidence has provided strong arguments for a causal and independent association between elevated Lp(a) levels and CVD, causing renewed interest in this lipoprotein as an emerging risk factor with a likely contribution to cardiovascular residual risk. Accordingly, the 2022 consensus statement of the European Atherosclerosis Society has suggested inclusion of Lp(a) measurement in global risk estimation. The development of highly effective Lp(a)-lowering drugs (e.g., antisense oligonucleotides and small interfering RNA, both blocking LPA gene expression) which are still under assessment in phase 3 trials, will provide a unique opportunity to reduce “residual cardiovascular risk” in high-risk populations, including patients with arterial hypertension. The current evidence in support of a specific role of Lp(a) in hypertension is somehow controversial and this narrative review aims to overview the general mechanisms relating Lp(a) to blood pressure regulation and hypertension-related cardiovascular and renal damage. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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12 pages, 575 KiB  
Review
Exploring the Association between Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes—A Comprehensive Review
by Laura Adina Stanciulescu, Alexandru Scafa-Udriste and Maria Dorobantu
Int. J. Mol. Sci. 2023, 24(7), 6669; https://doi.org/10.3390/ijms24076669 - 3 Apr 2023
Cited by 5 | Viewed by 2209
Abstract
Cardiovascular disease (CVD) impacts hundreds of millions of people each year and is the main cause of death worldwide, with atherosclerosis being its most frequent form of manifestation. Low-density lipoproteins (LDL) have already been established as a significant cardiovascular risk factor, but more [...] Read more.
Cardiovascular disease (CVD) impacts hundreds of millions of people each year and is the main cause of death worldwide, with atherosclerosis being its most frequent form of manifestation. Low-density lipoproteins (LDL) have already been established as a significant cardiovascular risk factor, but more recent studies have shown that small, dense LDLs are the ones more frequently associated with a higher overall risk for developing atherosclerotic cardiovascular disease. Ever since atherogenic phenotypes were defined for the first time, LDL subfractions have been continuously analyzed in order to identify those with a higher atherogenic profile that could further become not only high-accuracy, effective prognostic biomarkers, but also treatment targets for novel lipid-lowering molecules. This review sets out to comprehensively evaluate the association between various LDL-subfractions and the risk of further developing major adverse cardiovascular events, by assessing both genetical and clinical features and focusing on their physiopathological characteristics, chemical composition, and global ability to predict long-term cardiovascular risk within the general population. Further research is required in order to establish the most beneficial range of LDL-C levels for both primary and secondary prevention, as well as to implement LDL subfraction testing as a routine protocol, separately from the general assessment of the other traditional cardiovascular risk factors. Full article
(This article belongs to the Special Issue Lipoprotein Metabolism in Health and Disease)
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