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The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Lipid Metabolism".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 14504

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Special Issue Editors

Prof. Dr. Ta-Chen Su

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Guest Editor

1. Department of Environmental and Occupational Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 10002, Taiwan
2. Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan
3. Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 10057, Taiwan
Interests: atherosclerosis; atrial fibrillation; cardiovascular; epidemiology and public health; epidemiology; lipoproteins; cardiovascular risk

Prof. Dr. Shizuya Yamashita

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Guest Editor

Department of Cardiology, Rinku General Medical Center, 2-23 Ourai-kita, Rinku, Izumisano, Osaka 598-8577, Japan
Interests: cardiology; metabolism; clinical lipidology; lipoprotein; treatment of dyslipidemia; pathogenesis of atherosclerosis; metabolic syndrome

Prof. Dr. Manfredi Rizzo

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Guest Editor

Department of Internal Medicine and Medical Specialties (DIMIS), Università degli Studi di Palermo UNIPA, 90100 Palermo, Italy
Interests: cardiovascular risk; lipids; diabetes; prevention; therapy; metabolic syndrome; metabolism; lipoproteins; incretins; nutraceuticals
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Special Issue Information

Dear Colleagues,

This Special Issue defines lipids and lipid metabolisms, including different classes and types of lipids and lipid-containing particles, the metabolism of lipids in the cells and tissues, lipid transport, etc. Reviews and research articles that summarize and investigate the role of lipids in physiological processes, metabolism, pathology, and disease are very welcome. In addition to low-density lipoprotein cholesterol (LDL-C), atherogenic dyslipidemia including higher levels of triglycerides, VLDL-C, small dense LDL-C, lipoprotein (a), Apolipoprotein B, non-HDL, and total to high-density lipoprotein cholesterol (TC/HDL-C) ratio and lower levels of HDL-C, etc., are reported to increase the risk of atherosclerotic cardiovascular diseases (ASCVDs). This Special Issue aims to publish translational medicine to apply the results of basic research into the management of various diseases, particularly in lipid metabolism and CVDs. Lifestyle, nutritional status and eating habits that relate to atherogenic dyslipidemia and ASCVDs are also welcome.

The Special Issue focuses on atherosclerosis. LDL-C is a well-established risk factor for atherosclerosis. TC/HDL-C ratio as a CVDs risk factor has also gained much attention. Compared with using an LDL-C level as the cut-off point, using a TC/HDL-C ratio was associated with superior specificity and accuracy in predicting future coronary heart disease. The TC/HDL-C ratio also reclassifies atheroma progression and MACE rates when discordant with LDL-C, non-HDL-C, and ApoB within patients. Extra- and intracellular atherosclerosis development, predominantly the deposition of lipids and cholesteryl esters in arterial intima, is one of the earliest manifestations of atherosclerosis. LDL-C circulating in human blood is the source of lipids accumulated in arterial cells. LDL particles must undergo chemical modification before the initiation of atherosclerosis. Measurable biomarkers in blood, in such forms as oxidized, small dense, and electronegative, have been described as pro-atherogenic LDLs. Studies of the pathogenic basis of modified LDLs on atherosclerosis and CVDs may shed light on preventive cardiology.

Inflammation has also been found to play a pivotal role, independent of lipoprotein levels, in the development and progression of ASCVDs. Retrospective and prospective studies have found that hsCRP elevation is associated with CVD events. The synergistic effects of inflammation and atherogenic dyslipidemia may respresent another aspect of the proactive prevention of ASCVDs. Establishing the relationship between modified LDL, dysfunctional HDL, and inflammation is extremely important for elucidating the mechanisms of atherogenesis, since both atherogenic dyslipidemia and chronic inflammation are closely associated with atherosclerotic lesion initiation and subsequently the development of ASCVDs.

The purpose of this Special Issue is to collect current knowledge on the role of lipid-related causes and metabolisms in the pathogenesis of various ASCVDs. Understanding the causes and characteristics of the lipid disorders leading to ASCVDs can provide the basis for new diagnostic and therapeutic approaches in public health education and clinical practice.

Prof. Dr. Ta-Chen Su
Prof. Dr. Shizuya Yamashita
Prof. Dr. Manfredi Rizzo
Guest Editors

Manuscript Submission Information

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Keywords

atherogenic dyslipidemia
atherosclerosis
diagnostics
atherosclerotic cardiovascular diseases
coronary heart disease
high-density lipoprotein
inflammation
low-density lipoprotein
modified LDLs
subpopulations of lipids
lipid-containing particles
lipid metabolism
pathology
lipidomics

Published Papers (7 papers)

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Research

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19 pages, 9623 KiB

Open AccessArticle

Alterations of NMR-Based Lipoprotein Profile Distinguish Unstable Angina Patients with Different Severity of Coronary Lesions

by Yongxin Ye, Jiahua Fan, Zhiteng Chen, Xiuwen Li, Maoxiong Wu, Wenhao Liu, Shiyi Zhou, Morten Arendt Rasmussen, Søren Balling Engelsen, Yangxin Chen, Bekzod Khakimov and Min Xia

Metabolites 2023, 13(2), 273; https://doi.org/10.3390/metabo13020273 - 14 Feb 2023

Cited by 1 | Viewed by 1317

Abstract

Non-invasive detection of unstable angina (UA) patients with different severity of coronary lesions remains challenging. This study aimed to identify plasma lipoproteins (LPs) that can be used as potential biomarkers for assessing the severity of coronary lesions, determined by the Gensini score (GS), in UA patients. We collected blood plasma from 67 inpatients with angiographically normal coronary arteries (NCA) and 230 UA patients, 155 of them with lowGS (GS ≤ 25.4) and 75 with highGS (GS > 25.4), and analyzed it using proton nuclear magnetic resonance spectroscopy to quantify 112 lipoprotein variables. In a logistic regression model adjusted for four well-known risk factors (age, sex, body mass index and use of lipid-lowering drugs), we tested the association between each lipoprotein and the risk of UA. Combined with the result of LASSO and PLS-DA models, ten of them were identified as important LPs. The discrimination with the addition of selected LPs was evaluated. Compared with the basic logistic model that includes four risk factors, the addition of these ten LPs concentrations did not significantly improve UA versus NCA discrimination. However, thirty-two selected LPs showed notable discrimination power in logistic regression modeling distinguishing highGS UA patients from NCA with a 14.9% increase of the area under the receiver operating characteristics curve. Among these LPs, plasma from highGS patients was enriched with LDL and VLDL subfractions, but lacked HDL subfractions. In summary, we conclude that blood plasma lipoproteins can be used as biomarkers to distinguish UA patients with severe coronary lesions from NCA patients. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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11 pages, 979 KiB

Open AccessArticle

Capacity of HDL to Efflux Cellular Cholesterol from Lipid-Loaded Macrophages Is Reduced in Patients with Familial Hypercholesterolemia

by Shiva Ganjali, Susan Hosseini, Manfredi Rizzo, Anatol Kontush and Amirhossein Sahebkar

Metabolites 2023, 13(2), 197; https://doi.org/10.3390/metabo13020197 - 29 Jan 2023

Cited by 3 | Viewed by 1149

Abstract

This study aimed to evaluate the high-density lipoprotein (HDL) capacity to efflux cellular cholesterol from lipid-loaded macrophages to find a reliable and low-cost biomarker with the purpose of better evaluating the risk of premature cardiovascular (CV) events in FH patients. This case-controlled study comprised 16 homozygous (HOFH) and 18 heterozygous (HEFH) FH patients, as well as 20 healthy subjects recruited as controls. Two main subfractions of HDL (HDL2 (d = 1.063–1.125 g/mL) and HDL3 (d = 1.125–1.210 g/mL)) were isolated from the patients’ serum samples using sequential ultracentrifugation. After compositional characterization, the capacity of HDL to efflux cholesterol (CEC%) from lipid-laden macrophages was measured. The HDL2 and HDL3 subfractions showed some differences in lipid and protein composition between the studied groups. In addition, both HDL subfractions (p < 0.001) revealed significantly reduced CEC% in HOFH patients (HDL2: 2.5 ± 0.1 and HDL3: 3.2 ± 0.2) in comparison with the HEFH (HDL2: 3.2 ± 0.1% and HDL3: 4.1 ± 0.2%) and healthy (HDL2: 3.3 ± 0.2% and HDL3: 4.5 ± 0.3%) subjects. Additionally, multinomial logistic regression results indicated that the CEC% of both HDL2 (OR: 0.091; 95% CI: 0.018–0.452, p < 0.01) and HDL3 (OR: 0.118; 95% CI: 0.035–0.399, p < 0.01) subfractions are strongly and inversely associated with the homozygous form of FH. A decreased capacity of HDL particles to efflux cholesterol from macrophages might identify homozygous FH patients who are at elevated risk for premature CVDs. Prospective studies with a large sample size are warranted to evaluate this hypothesis. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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23 pages, 25428 KiB

Open AccessArticle

Identification of a Chromosome 1 Substitution Line B6-Chr1BLD as a Novel Hyperlipidemia Model via Phenotyping Screening

by Xu Li, Minli Sun, Hao Qi, Cunxiang Ju, Zhong Chen, Xiang Gao and Zhaoyu Lin

Metabolites 2022, 12(12), 1276; https://doi.org/10.3390/metabo12121276 - 16 Dec 2022

Cited by 1 | Viewed by 1738

Abstract

Hyperlipidemia is a chronic disease that seriously affects human health. Due to the fact that traditional animal models cannot fully mimic hyperlipidemia in humans, new animal models are urgently needed for basic drug research on hyperlipidemia. Previous studies have demonstrated that the genomic diversity of the wild mice chromosome 1 substitution lines was significantly different from that of laboratory mice, suggesting that it might be accompanied by phenotypic diversity. We first screened the blood lipid-related phenotype of chromosome 1 substitution lines. We found that the male HFD-fed B6-Chr1BLD mice showed more severe hyperlipidemia-related phenotypes in body weight, lipid metabolism and liver lesions. By RNA sequencing and whole-genome sequencing results of B6-Chr1BLD, we found that several differentially expressed single nucleotide polymorphism enriched genes were associated with lipid metabolism-related pathways. Lipid metabolism-related genes, mainly including Aida, Soat1, Scly and Ildr2, might play an initial and upstream role in the abnormal metabolic phenotype of male B6-Chr1BLD mice. Taken together, male B6-Chr1BLD mice could serve as a novel, polygenic interaction-based hyperlipidemia model. This study could provide a novel animal model for accurate clinical diagnosis and precise medicine of hyperlipidemia. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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12 pages, 1663 KiB

Open AccessArticle

The Level of Remnant Cholesterol and Implications for Lipid-Lowering Strategy in Hospitalized Patients with Acute Coronary Syndrome in China: Findings from the Improving Care for Cardiovascular Disease in China—Acute Coronary Syndrome Project

by Na Yang, Miao Wang, Jing Liu, Jun Liu, Yongchen Hao, Dong Zhao and on behalf of CCC-ACS Investigators

Metabolites 2022, 12(10), 898; https://doi.org/10.3390/metabo12100898 - 24 Sep 2022

Cited by 4 | Viewed by 1858

Abstract

Elevated remnant cholesterol is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the concentrations and general distribution of remnant cholesterol at admission in patients hospitalized for acute coronary syndrome (ACS), and those in patients who reached the low-density lipoprotein cholesterol (LDL-C) target or non-high-density lipoprotein cholesterol (non-HDL-C) target. Patients with ACS who were enrolled in the Improving Care for Cardiovascular Disease in China—ACS project from 2014 to 2019 were included. Elevated remnant cholesterol concentrations were defined as ≥1.0 mmol/L. Among 94,869 patients, the median (interquartile range) remnant cholesterol concentration at admission was 0.6 mmol/L (0.4–0.9 mmol/L) and 19.2% had elevated remnant cholesterol concentrations. Among patients with LDL-C concentrations < 1.4 mmol/L, 24.4% had elevated remnant cholesterol concentrations, while the proportion was 13.3% among patients with LDL-C concentrations between 1.4 and 1.7 mmol/L. Among patients with non-HDL-C concentrations < 2.6 mmol/L, 2.9% had elevated remnant cholesterol concentrations but 79.6% had LDL-C concentrations ≥ 1.4 mmol/L. Even among patients with LDL-C < 1.4 mmol/L and non-HDL-C < 2.6 mmol/L, 10.9% had elevated remnant cholesterol. In conclusion, one fifth of patients with ACS have elevated remnant cholesterol concentrations at admission. Elevated remnant cholesterol concentrations are present in patients with LDL-C or/and non-HDL-C concentrations within the target, which represents an unmet need to add remnant cholesterol as a target for the secondary prevention of ASCVD. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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Review

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21 pages, 684 KiB

Open AccessReview

Appropriateness of Dyslipidemia Management Strategies in Post-Acute Coronary Syndrome: A 2023 Update

by Fabiana Lucà, Fabrizio Oliva, Carmelo Massimiliano Rao, Maurizio Giuseppe Abrignani, Antonio Francesco Amico, Stefania Angela Di Fusco, Giorgio Caretta, Irene Di Matteo, Concetta Di Nora, Anna Pilleri, Roberto Ceravolo, Roberta Rossini, Carmine Riccio, Massimo Grimaldi, Furio Colivicchi and Michele Massimo Gulizia

Metabolites 2023, 13(8), 916; https://doi.org/10.3390/metabo13080916 - 04 Aug 2023

Cited by 4 | Viewed by 1962

Abstract

It has been consistently demonstrated that circulating lipids and particularly low-density lipoprotein cholesterol (LDL-C) play a significant role in the development of coronary artery disease (CAD). Several trials have been focused on the reduction of LDL-C values in order to interfere with atherothrombotic progression. Importantly, for patients who experience acute coronary syndrome (ACS), there is a 20% likelihood of cardiovascular (CV) event recurrence within the two years following the index event. Moreover, the mortality within five years remains considerable, ranging between 19 and 22%. According to the latest guidelines, one of the main goals to achieve in ACS is an early improvement of the lipid profile. The evidence-based lipid pharmacological strategy after ACS has recently been enhanced. Although novel lipid-lowering drugs have different targets, the result is always the overexpression of LDL receptors (LDL-R), increased uptake of LDL-C, and lower LDL-C plasmatic levels. Statins, ezetimibe, and PCSK9 inhibitors have been shown to be safe and effective in the post-ACS setting, providing a consistent decrease in ischemic event recurrence. However, these drugs remain largely underprescribed, and the consistent discrepancy between real-world data and guideline recommendations in terms of achieved LDL-C levels represents a leading issue in secondary prevention. Although the cost-effectiveness of these new therapeutic advancements has been clearly demonstrated, many concerns about the cost of some newer agents continue to limit their use, affecting the outcome of patients who experienced ACS. In spite of the fact that according to the current recommendations, a stepwise lipid-lowering approach should be adopted, several more recent data suggest a "strike early and strike strong" strategy, based on the immediate use of statins and, eventually, a dual lipid-lowering therapy, reducing as much as possible the changes in lipid-lowering drugs after ACS. This review aims to discuss the possible lipid-lowering strategies in post-ACS and to identify those patients who might benefit most from more powerful treatments and up-to-date management. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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14 pages, 1815 KiB

Open AccessReview

The Role of Advanced Glycation End Products on Dyslipidemia

by Jelena Vekic, Sanja Vujcic, Biljana Bufan, Dragana Bojanin, Khamis Al-Hashmi, Khaild Al-Rasadi, Anca Pantea Stoian, Aleksandra Zeljkovic and Manfredi Rizzo

Metabolites 2023, 13(1), 77; https://doi.org/10.3390/metabo13010077 - 03 Jan 2023

Cited by 8 | Viewed by 2882

Abstract

Disorders of lipoprotein metabolism and glucose homeostasis are common consequences of insulin resistance and usually co-segregate in patients with metabolic syndrome and type 2 diabetes mellitus (DM). Insulin-resistant subjects are characterized by atherogenic dyslipidemia, a specific lipid pattern which includes hypertriglyceridemia, reduced high-density lipoprotein cholesterol level, and increased proportion of small, dense low-density lipoprotein (LDL). Chronic hyperglycemia favors the processes of non-enzymatic glycation, leading to the increased production of advanced glycation end products (AGEs). Apart from direct harmful effects, AGEs are also potent inducers of oxidative stress and inflammation. In addition, increased AGEs’ production may induce further qualitative modifications of small, dense LDL particles, converting them to glycated LDLs. These particles are even more atherogenic and may confer an increased cardiovascular risk. In this narrative review, we summarize the available evidence of the pathophysiological role and clinical importance of circulating AGEs and glycated LDLs in patients with dyslipidemia, particularly those with DM and related complications. In addition, we discuss recent advances and the issues that should be improved regarding laboratory assessment of AGEs and glycated LDLs, as well as the possibilities for their therapeutic modulation. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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12 pages, 310 KiB

Open AccessReview

Familial Hypercholesterolemia and Lipoprotein(a): A Gordian Knot in Cardiovascular Prevention

by Amalia Despoina Koutsogianni, Petros Spyridonas Adamidis, Fotios Barkas, Evangelos Liberopoulos, Ta-Chen Su, Shizuya Yamashita, George Liamis and Manfredi Rizzo

Metabolites 2022, 12(11), 1065; https://doi.org/10.3390/metabo12111065 - 04 Nov 2022

Cited by 6 | Viewed by 1799

Abstract

Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000–400,000 for the homozygous and ~1:200–300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (>50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been recently developed and their cardiovascular efficacy is currently investigated. Although a considerable proportion of FH patients is also diagnosed with high Lp(a) levels, there is a debate whether these two entities are associated. Nevertheless, Lp(a), particularly among patients with FH, has been established as a significant cardiovascular risk factor. In this narrative review, we present up-to-date evidence on the pathophysiology, diagnosis, and treatment of both FH and elevated Lp(a) with a special focus on their association and joint effect on ASCVD risk. Full article

(This article belongs to the Special Issue The Role of Lipid Metabolism in Dyslipidemias and Atherosclerosis)

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