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Cholesterol and Lipoprotein Metabolism 2.0

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

Deadline for manuscript submissions: closed (25 December 2023) | Viewed by 11704

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Prof. Dr. Bart De Geest

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Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49 bus 911, 3000 Leuven, Belgium
Interests: lipoproteins; atherosclerosis; coronary heart disease; familial hypercholesterolemia; low-density lipoprotein (LDL) receptor; heart failure; gene therapy
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Dear Colleagues,

Cholesterol is an essential structural component of all animal cell membranes. It was isolated from gallstones by the French doctor and chemist François Poulletier de la Salle in 1758. Cholesterol is a determinant of both cell membrane structural integrity and fluidity, and is critical for cell and organ function. The German chemist and Nobel Prize winner A. Windaus reported in 1910 that atherosclerotic plaques from human aortas contained over 20-fold higher concentrations of cholesterol than normal aortas did. Since then, several lines of evidence have established a causal connection between blood cholesterol, atherosclerosis, and coronary heart disease.

All proatherogenic lipoproteins contain apolipoprotein B. The retention of proatherogenic lipoproteins within the vessel wall is the obligatory initiating event of atherogenesis. The retained lipoproteins trigger an inflammatory response that is accompanied by lesion progression and the formation of advanced atherosclerotic plaques. Increased remnant lipoproteins are considered to constitute an important determinant of residual cardiovascular risk in patients with adequately lowered levels of low-density lipoprotein cholesterol.

The scientific fields of cholesterol homeostasis, lipoprotein metabolism, atherosclerosis, and ischemic heart disease remain inexhaustible sources of challenging questions and discovery. This Special Issue will cover recent advances in these fields.

Prof. Dr. Bart De Geest
Guest Editor

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Keywords

cholesterol
lipoproteins
atherosclerosis
coronary heart disease
remnant lipoproteins
low-density lipoproteins
apolipoprotein B

Published Papers (7 papers)

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Research

15 pages, 3096 KiB

Open AccessArticle

Proteomic Determinants of Variation in Cholesterol Efflux: Observations from the Dallas Heart Study

by Anamika Gangwar, Sneha S. Deodhar, Suzanne Saldanha, Olle Melander, Fahim Abbasi, Ryan W. Pearce, Timothy S. Collier, Michael J. McPhaul, Jeremy D. Furtado, Frank M. Sacks, Nathaniel J. Merrill, Jason E. McDermott, John T. Melchior and Anand Rohatgi

Int. J. Mol. Sci. 2023, 24(21), 15526; https://doi.org/10.3390/ijms242115526 - 24 Oct 2023

Viewed by 991

Abstract

High-density lipoproteins (HDLs) are promising targets for predicting and treating atherosclerotic cardiovascular disease (ASCVD), as they mediate removal of excess cholesterol from lipid-laden macrophages that accumulate in the vasculature. This functional property of HDLs, termed cholesterol efflux capacity (CEC), is inversely associated with ASCVD. HDLs are compositionally diverse, associating with >250 different proteins, but their relative contribution to CEC remains poorly understood. Our goal was to identify and define key HDL-associated proteins that modulate CEC in humans. The proteomic signature of plasma HDL was quantified in 36 individuals in the multi-ethnic population-based Dallas Heart Study (DHS) cohort that exhibited persistent extremely high (>=90th%) or extremely low CEC (<=10th%) over 15 years. Levels of apolipoprotein (Apo)A-I associated ApoC-II, ApoC-III, and ApoA-IV were differentially correlated with CEC in high (r = 0.49, 0.41, and −0.21 respectively) and low (r = −0.46, −0.41, and 0.66 respectively) CEC groups (p for heterogeneity (pHet) = 0.03, 0.04, and 0.003 respectively). Further, we observed that levels of ApoA-I with ApoC-III, complement C3 (CO3), ApoE, and plasminogen (PLMG) were inversely associated with CEC in individuals within the low CEC group (r = −0.11 to −0.25 for subspecies with these proteins vs. r = 0.58 to 0.65 for subspecies lacking these proteins; p < 0.05 for heterogeneity). These findings suggest that enrichment of specific proteins on HDLs and, thus, different subspecies of HDLs, differentially modulate the removal of cholesterol from the vasculature. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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15 pages, 2874 KiB

Open AccessArticle

LOX-1 Activation by oxLDL Induces AR and AR-V7 Expression via NF-κB and STAT3 Signaling Pathways Reducing Enzalutamide Cytotoxic Effects

by Felix Duprat, Catalina Robles, María Paz Castillo, Yerko Rivas, Marcela Mondaca, Nery Jara, Francisco Roa, Romina Bertinat, Jorge Toledo, Cristian Paz and Iván González-Chavarría

Int. J. Mol. Sci. 2023, 24(6), 5082; https://doi.org/10.3390/ijms24065082 - 07 Mar 2023

Cited by 5 | Viewed by 1922

Abstract

The oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for modified LDLs, such as oxidated (oxLDL) and acetylated (acLDL) low-density lipoprotein. LOX-1 and oxLDL are fundamental in atherosclerosis, where oxLDL/LOX1 promotes ROS generation and NF-κB activation inducing the expression of IL-6, a STAT3 activator. Furthermore, LOX-1/oxLDL function has been associated with other diseases, such as obesity, hypertension, and cancer. In prostate cancer (CaP), LOX-1 overexpression is associated with advanced stages, and its activation by oxLDL induces an epithelial-mesenchymal transition, increasing angiogenesis and proliferation. Interestingly, enzalutamide-resistant CaP cells increase the uptake of acLDL. Enzalutamide is an androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) treatment, and a high percentage of patients develop a resistance to this drug. The decreased cytotoxicity is promoted in part by STAT3 and NF-κB activation that induces the secretion of the pro-inflammatory program and the expression of AR and its splicing variant AR-V7. Here, we demonstrate for the first time that oxLDL/LOX-1 increases ROS levels and activates NF-κB, inducing IL-6 secretion and the activation of STAT3 in CRPC cells. Furthermore, oxLDL/LOX1 increases AR and AR-V7 expression and decreases enzalutamide cytotoxicity in CRPC. Thus, our investigation suggests that new factors associated with cardiovascular pathologies, such as LOX-1/oxLDL, may also promote important signaling axes for the progression of CRPC and its resistance to drugs used for its treatment. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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15 pages, 2437 KiB

Open AccessArticle

Oxidized Low-Density Lipoproteins Trigger Hepatocellular Oxidative Stress with the Formation of Cholesteryl Ester Hydroperoxide-Enriched Lipid Droplets

by Iku Sazaki, Toshihiro Sakurai, Arisa Yamahata, Sumire Mogi, Nao Inoue, Koutaro Ishida, Ami Kikkai, Hana Takeshita, Akiko Sakurai, Yuji Takahashi, Hitoshi Chiba and Shu-Ping Hui

Int. J. Mol. Sci. 2023, 24(5), 4281; https://doi.org/10.3390/ijms24054281 - 21 Feb 2023

Cited by 3 | Viewed by 1808

Abstract

Oxidized low-density lipoproteins (oxLDLs) induce oxidative stress in the liver tissue, leading to hepatic steatosis, inflammation, and fibrosis. Precise information on the role of oxLDL in this process is needed to establish strategies for the prevention and management of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Here, we report the effects of native LDL (nLDL) and oxLDL on lipid metabolism, lipid droplet formation, and gene expression in a human liver-derived C3A cell line. The results showed that nLDL induced lipid droplets enriched with cholesteryl ester (CE) and promoted triglyceride hydrolysis and inhibited oxidative degeneration of CE in association with the altered expression of LIPE, FASN, SCD1, ATGL, and CAT genes. In contrast, oxLDL showed a striking increase in lipid droplets enriched with CE hydroperoxides (CE-OOH) in association with the altered expression of SREBP1, FASN, and DGAT1. Phosphatidylcholine (PC)-OOH/PC was increased in oxLDL-supplemented cells as compared with other groups, suggesting that oxidative stress increased hepatocellular damage. Thus, intracellular lipid droplets enriched with CE-OOH appear to play a crucial role in NAFLD and NASH, triggered by oxLDL. We propose oxLDL as a novel therapeutic target and candidate biomarker for NAFLD and NASH. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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17 pages, 905 KiB

Open AccessArticle

Effect of Clinical and Laboratory Parameters on HDL Particle Composition

by Christina E. Kostara, Eleni T. Bairaktari and Vasilis Tsimihodimos

Int. J. Mol. Sci. 2023, 24(3), 1995; https://doi.org/10.3390/ijms24031995 - 19 Jan 2023

Cited by 4 | Viewed by 1193

Abstract

The functional status of High-Density Lipoprotein (HDLs) is not dependent on the cholesterol content but is closely related to structural and compositional characteristics. We reported the analysis of HDL lipidome in the healthy population and the influence of serum lipids, age, gender and menopausal status on its composition. Our sample comprised 90 healthy subjects aged between 30 and 77 years. HDL lipidome was investigated by Nuclear Magnetic Resonance (NMR) spectroscopy. Among serum lipids, triglycerides, apoAI, apoB and the ratio HDL-C/apoAI had a significant influence on HDL lipid composition. Aging was associated with significant aberrations, including an increase in triglyceride content, lysophosphatidylcholine, free cholesterol, and a decrease in esterified cholesterol, phospholipids, and sphingomyelin that may contribute to increased cardiovascular risk. Aging was also associated with an atherogenic fatty acid pattern. Changes occurring in the HDL lipidome between the two genders were more pronounced in the decade from 30 to 39 years of age and over 60 years. The postmenopausal group displayed significant pro-atherogenic changes in HDLs compared to the premenopausal group. The influence of serum lipids and intrinsic factors on HDL lipidome could improve our understanding of the remodeling capacity of HDLs directly related to its functionality and antiatherogenic properties, and also in appropriate clinical research study protocol design. These data demonstrate that NMR analysis can easily follow the subtle alterations of lipoprotein composition due to serum lipid parameters. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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17 pages, 4813 KiB

Open AccessArticle

Metabolomics and Proteomics Characterizing Hepatic Reactions to Dietary Linseed Oil in Duck

by Yang Zhang, Ao Zhang, Laidi Wang, Ting Yang, Bingqiang Dong, Zhixiu Wang, Yulin Bi, Guohong Chen and Guobin Chang

Int. J. Mol. Sci. 2022, 23(24), 15690; https://doi.org/10.3390/ijms232415690 - 10 Dec 2022

Cited by 2 | Viewed by 1822

Abstract

The imbalance in polyunsaturated fatty acid (PUFA) composition in human food is ubiquitous and closely related to obesity and cardiovascular diseases. The development of n-3 PUFA-enriched poultry products is of great significance for optimizing fatty acid composition. This study aimed to improve our understanding of the effects of dietary linseed oil on hepatic metabolism using untargeted metabolomics and 4D label-free proteome analysis. A total of 91 metabolites and 63 proteins showed differences in abundance in duck livers between the high linseed oil and control groups. Pathway analysis revealed that the biosynthesis of unsaturated fatty acids, linoleic acid, glycerophospholipid, and pyrimidine metabolisms were significantly enriched in ducks fed with linseed oil. Meanwhile, dietary linseed oil changed liver fatty acid composition, which was reflected in the increase in the abundance of downstream metabolites, such as α-linolenic acid (ALA; 18:3n-3) as a substrate, including n-3 PUFA and its related glycerophospholipids, and a decrease in downstream n-6 PUFA synthesis using linoleic acid (LA; 18:2n-6) as a substrate. Moreover, the anabolism of PUFA in duck livers showed substrate-dependent effects, and the expression of related proteins in the process of fatty acid anabolism, such as FADS2, LPIN2, and PLA2G4A, were significantly regulated by linseed oil. Collectively, our work highlights the ALA substrate dependence during n-3 PUFA synthesis in duck livers. The present study expands our knowledge of the process products of PUFA metabolism and provides some potential biomarkers for liver health. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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29 pages, 18407 KiB

Open AccessArticle

Effect of the First Feeding on Enterocytes of Newborn Rats

by Maria A. Nikonova, Irina S. Sesorova, Ivan D. Dimov, Natalia R. Karelina and Alexander A. Mironov

Int. J. Mol. Sci. 2022, 23(22), 14179; https://doi.org/10.3390/ijms232214179 - 16 Nov 2022

Cited by 6 | Viewed by 1641

Abstract

The transcytosis of lipids through enterocytes occurs through the delivery of lipid micelles to the microvilli of enterocytes, consumption of lipid derivates by the apical plasma membrane (PM) and then their delivery to the membrane of the smooth ER attached to the basolateral PM. The SER forms immature chylomicrons (iChMs) in the ER lumen. iChMs are delivered at the Golgi complex (GC) where they are subjected to additional glycosylation resulting in maturation of iChMs. ChMs are secreted into the intercellular space and delivered into the lumen of lymphatic capillaries (LCs). The overloading of enterocytes with lipids induces the formation of lipid droplets inside the lipid bilayer of the ER membranes and transcytosis becomes slower. Here, we examined components of the enterocyte-to-lymphatic barriers in newly born rats before the first feeding and after it. In contrast to adult animals, enterocytes of newborns rats exhibited apical endocytosis and a well-developed subapical endosomal tubular network. These enterocytes uptake membranes from amniotic fluid. Then these membranes are transported across the polarized GC and secreted into the intercellular space. The enterocytes did not contain COPII-coated buds on the granular ER. The endothelium of blood capillaries situated near the enterocytes contained only a few fenestrae. The LCs were similar to those in adult animals. The first feeding induced specific alterations of enterocytes, which were similar to those observed after the lipid overloading of enterocytes in adult rats. Enlarged chylomicrons were stopped at the level of the LAMP2 and Neu1 positive post-Golgi structures, secreted, fused, delivered to the interstitial space, captured by the LCs and transported to the lymph node, inducing the movement of macrophages from lymphatic follicles into its sinuses. The macrophages captured the ChMs, preventing their delivery into the blood. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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12 pages, 6697 KiB

Open AccessArticle

YM750, an ACAT Inhibitor, Acts on Adrenocortical Cells to Inhibit Aldosterone Secretion Due to Depolarization

by Hiroki Shimada, Shuko Hata, Yuto Yamazaki, Yuri Otsubo, Ikuko Sato, Kazue Ise, Atsushi Yokoyama, Takashi Suzuki, Hironobu Sasano, Akira Sugawara and Yasuhiro Nakamura

Int. J. Mol. Sci. 2022, 23(21), 12803; https://doi.org/10.3390/ijms232112803 - 24 Oct 2022

Cited by 1 | Viewed by 1510

Abstract

Primary aldosteronism (PA) is considered the most common form of secondary hypertension, which is associated with excessive aldosterone secretion in the adrenal cortex. The cause of excessive aldosterone secretion is the induction of aldosterone synthase gene (CYP11B2) expression by depolarization of adrenocortical cells. In this study, we found that YM750, an Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, acts on adrenocortical cells to suppress CYP11B2 gene expression and aldosterone secretion. YM750 inhibited the induction of CYP11B2 gene expression by KCl stimulation, but not by angiotensin II and forskolin stimulation. Interestingly, YM750 did not inhibit KCl-stimulated depolarization via an increase in intracellular calcium ion concentration. Moreover, ACAT1 expression was relatively abundant in the zona glomerulosa (ZG) including these CYP11B2-positive cells. Thus, YM750 suppresses CYP11B2 gene expression by suppressing intracellular signaling activated by depolarization. In addition, ACAT1 was suggested to play an important role in steroidogenesis in the ZG. YM750 suppresses CYP11B2 gene expression and aldosterone secretion in the adrenal cortex, suggesting that it may be a potential therapeutic agent for PA. Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism 2.0)

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