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Arteriosclerosis, Thrombosis, and... Jul 2023APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density... (Review)
Review
APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density lipoprotein, respectively. The 4 smaller APOCs (APOC1, APOC2, APOC3, and APOC4) are exchangeable apolipoproteins; they are readily transferred among high-density lipoproteins and APOB-containing lipoproteins. The APOCs regulate plasma triglyceride and cholesterol levels by modulating substrate availability and activities of enzymes interacting with lipoproteins and by interfering with APOB-containing lipoprotein uptake through hepatic receptors. Of the 4 APOCs, APOC3 has been best studied in relation to diabetes. Elevated serum APOC3 levels predict incident cardiovascular disease and progression of kidney disease in people with type 1 diabetes. Insulin suppresses APOC3 levels, and accordingly, elevated APOC3 levels associate with insulin deficiency and insulin resistance. Mechanistic studies in a mouse model of type 1 diabetes have demonstrated that APOC3 acts in the causal pathway of diabetes-accelerated atherosclerosis. The mechanism is likely due to the ability of APOC3 to slow the clearance of triglyceride-rich lipoproteins and their remnants, thereby causing an increased accumulation of atherogenic lipoprotein remnants in lesions of atherosclerosis. Less is known about the roles of APOC1, APOC2, and APOC4 in diabetes.
Topics: Mice; Animals; Apolipoprotein C-II; Diabetes Mellitus, Type 1; Lipoproteins; Triglycerides; Lipoproteins, HDL; Apolipoprotein C-III; Lipoproteins, LDL; Atherosclerosis; Apolipoproteins B; Insulins
PubMed: 37226733
DOI: 10.1161/ATVBAHA.122.318290 -
Current Opinion in Lipidology Jun 2022Levels of small, dense low-density lipoprotein (LDL) (sdLDL) particles determined by several analytic procedures have been associated with risk of atherosclerotic... (Review)
Review
PURPOSE OF REVIEW
Levels of small, dense low-density lipoprotein (LDL) (sdLDL) particles determined by several analytic procedures have been associated with risk of atherosclerotic cardiovascular disease (ASCVD). This review focuses on the clinical significance of sdLDL measurement.
RECENT FINDINGS
Results of multiple prospective studies have supported earlier evidence that higher levels of sdLDL are significantly associated with greater ASCVD risk, in many cases independent of other lipid and ASCVD risk factors as well as levels of larger LDL particles. A number of properties of sdLDL vs. larger LDL, including reduced LDL receptor affinity and prolonged plasma residence time as well as greater oxidative susceptibility and affinity for arterial proteoglycans, are consistent with their heightened atherogenic potential. Nevertheless, determination of the extent to which sdLDL can preferentially impact ASCVD risk compared with other apoprotein B-containing lipoproteins has been confounded by their metabolic interrelationships and statistical collinearity, as well as differences in analytic procedures and definitions of sdLDL.
SUMMARY
A growing body of data points to sdLDL concentration as a significant determinant of ASCVD risk. Although future studies should be aimed at determining the clinical benefit of reducing sdLDL levels, there is sufficient evidence to warrant consideration of sdLDL measurement in assessing and managing risk of cardiovascular disease.
VIDEO ABSTRACT
https://www.dropbox.com/s/lioohr2ead7yx2p/zoom_0.mp4?dl=0.
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Humans; Lipoproteins; Prospective Studies; Risk Factors
PubMed: 35276699
DOI: 10.1097/MOL.0000000000000824 -
Drug Delivery Dec 2021Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents.... (Review)
Review
Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents. While the cellular recognition of well-known HDL-based carriers occurs via interactions with an HDL receptor, the selective delivery and uptake of LDL particles by target cells are more complex. The most well-known mode of LDL-based delivery is via the interaction between apolipoprotein B (Apo-B) - the main protein of LDL - and the low-density lipoprotein receptor (LDLR). LDLR is expressed in the liver, adipocytes, and macrophages, and thus selectively delivers LDL carriers to these cells and tissues. Moreover, the elevated expression of LDLR in tumor cells indicates a role for LDL in the targeted delivery of chemotherapy drugs. In addition, chronic inflammation associated with hypercholesterolemia (i.e., high levels of endogenous LDL) can be abated by LDL carriers, which outcompete the deleterious oxidized LDL for uptake by macrophages. In this case, synthetic LDL nanocarriers act as 'eat-me' signals and exploit mechanisms of native LDL uptake for targeted drug delivery and imaging. Lastly, recent studies have shown that the delivery of LDL-based nanocarriers to macrophages via fluid-phase pinocytosis is a promising tool for atherosclerosis imaging. Hence, the present review summarizes the use of natural and synthetic LDL-based carriers for drug delivery and imaging and discusses various mechanisms of targeting.
Topics: Animals; Atherosclerosis; Drug Carriers; Humans; Hypercholesterolemia; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Nanomedicine; Receptors, Lipoprotein
PubMed: 33594923
DOI: 10.1080/10717544.2021.1886199 -
Molecular Metabolism Mar 2023Over the past 40 years, there has been considerable research into the management and treatment of atherogenic lipid disorders. Although the majority of treatments and... (Review)
Review
Over the past 40 years, there has been considerable research into the management and treatment of atherogenic lipid disorders. Although the majority of treatments and management strategies for cardiovascular disease (CVD) center around targeting low-density lipoprotein cholesterol (LDL-C), there is mounting evidence for the residual CVD risk attributed to high triglyceride (TG) and lipoprotein(a) (Lp(a)) levels despite the presence of lowered LDL-C levels. Among the biological mechanisms for clearing TG-rich lipoproteins, the VLDL receptor (VLDLR) plays a key role in the trafficking and metabolism of lipoprotein particles in multiple tissues, but it is not ordinarily expressed in the liver. Since VLDLR is capable of binding and internalizing apoE-containing TG-rich lipoproteins as well as Lp(a), hepatic VLDLR expression has the potential for promoting clearance of these atherogenic particles from the circulation and managing the residual CVD risk not addressed by current lipid lowering therapies. This review provides an overview of VLDLR function and the potential for developing a genetic medicine based on liver-targeted VLDLR gene expression.
Topics: Cholesterol, LDL; Receptors, LDL; Genetic Therapy
PubMed: 36739970
DOI: 10.1016/j.molmet.2023.101685 -
Journal of Diabetes Investigation Oct 2023In diabetes, the impairment of insulin secretion and insulin resistance contribute to hypertriglyceridemia, as the enzymatic activity of lipoprotein lipase (LPL) depends... (Review)
Review
In diabetes, the impairment of insulin secretion and insulin resistance contribute to hypertriglyceridemia, as the enzymatic activity of lipoprotein lipase (LPL) depends on insulin action. The transport of LPL to endothelial cells and its enzymatic activity are maintained by the formation of lipolytic complex depending on the multiple positive (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 [GPIHBP1], apolipoprotein C-II [APOC2], APOA5, heparan sulfate proteoglycan [HSPG], lipase maturation factor 1 [LFM1] and sel-1 suppressor of lin-12-like [SEL1L]) and negative regulators (APOC1, APOC3, angiopoietin-like proteins [ANGPTL]3, ANGPTL4 and ANGPTL8). Among the regulators, GPIHBP1 is a crucial molecule for the translocation of LPL from parenchymal cells to the luminal surface of capillary endothelial cells, and maintenance of lipolytic activity; that is, hydrolyzation of triglyceride into free fatty acids and monoglyceride, and conversion from chylomicron to chylomicron remnant in the exogenous pathway and from very low-density lipoprotein to low-density lipoprotein in the endogenous pathway. The null mutation of GPIHBP1 causes severe hypertriglyceridemia and pancreatitis, and GPIGBP1 autoantibody syndrome also causes severe hypertriglyceridemia and recurrent episodes of acute pancreatitis. In patients with type 2 diabetes, the elevated serum triglyceride levels negatively correlate with circulating LPL levels, and positively with circulating APOC1, APOC3, ANGPTL3, ANGPTL4 and ANGPTL8 levels. In contrast, circulating GPIHBP1 levels are not altered in type 2 diabetes patients with higher serum triglyceride levels, whereas they are elevated in type 2 diabetes patients with diabetic retinopathy and nephropathy. The circulating regulators of lipolytic complex might be new biomarkers for lipid and glucose metabolism, and diabetic vascular complications.
Topics: Humans; Glycosylphosphatidylinositols; Diabetes Mellitus, Type 2; Endothelial Cells; Acute Disease; Pancreatitis; Hypertriglyceridemia; Carrier Proteins; Triglycerides; Lipoproteins, LDL; Lipoproteins, HDL; Angiopoietin-Like Protein 3; Proteins
PubMed: 37448184
DOI: 10.1111/jdi.14056 -
Cancer Research Communications Apr 2023Most cancer-related deaths are due to metastases. Systemic factors, such as lipid-enriched environments [as low-density lipoprotein (LDL)-cholesterol], favor breast...
UNLABELLED
Most cancer-related deaths are due to metastases. Systemic factors, such as lipid-enriched environments [as low-density lipoprotein (LDL)-cholesterol], favor breast cancer, including triple-negative breast cancer (TNBC) metastasis formation. Mitochondria metabolism impacts TNBC invasive behavior but its involvement in a lipid-enriched setting is undisclosed. Here we show that LDL increases lipid droplets, induces CD36 and augments TNBC cells migration and invasion and . LDL induces higher mitochondrial mass and network spread in migrating cells, in an actin remodeling-dependent manner, and transcriptomic and energetic analyses revealed that LDL renders TNBC cells dependent on fatty acids (FA) usage for mitochondrial respiration. Indeed, engagement on FA transport into the mitochondria is required for LDL-induced migration and mitochondrial remodeling. Mechanistically, LDL treatment leads to mitochondrial long-chain fatty acid accumulation and increased reactive oxygen species (ROS) production. Importantly, CD36 or ROS blockade abolished LDL-induced cell migration and mitochondria metabolic adaptations. Our data suggest that LDL induces TNBC cells migration by reprogramming mitochondrial metabolism, revealing a new vulnerability in metastatic breast cancer.
SIGNIFICANCE
LDL induces breast cancer cell migration that relies on CD36 for mitochondrial metabolism and network remodeling, providing an antimetastatic metabolic strategy.
Topics: Humans; Lipoproteins, LDL; Triple Negative Breast Neoplasms; Reactive Oxygen Species; Fatty Acids; Cell Movement
PubMed: 37377750
DOI: 10.1158/2767-9764.CRC-22-0394 -
Journal of Dental Research Jan 2024Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past...
Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 ( = 6,229) and Parogene ( = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants ( = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.
Topics: Humans; Prospective Studies; Triglycerides; Fatty Acids; Cholesterol; Lipoproteins, LDL; Inflammation; Glycoproteins; Pyruvates
PubMed: 37968796
DOI: 10.1177/00220345231203562 -
Progress in Lipid Research Nov 2023Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various... (Review)
Review
Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various particles, including lipids. Defective lipid handling can drive excessive lipid accumulation leading to foam cell formation, a key feature of various cardiometabolic conditions such as atherosclerosis, non-alcoholic fatty liver disease, and obesity. At the same time, intracellular lipid storage and foam cell formation can also be viewed as a protective and anti-lipotoxic mechanism against a lipid-rich environment and associated elevated lipid uptake. Traditionally, foam cell formation has primarily been linked to cholesterol uptake via native and modified low-density lipoproteins. However, other lipids, including non-esterified fatty acids and triacylglycerol (TAG)-rich lipoproteins (very low-density lipoproteins and chylomicrons), can also interact with macrophages. Recent studies have identified multiple pathways mediating TAG uptake and processing by macrophages, including endocytosis and receptor/transporter-mediated internalization and transport. This review will present the current knowledge of how macrophages take up different lipids and lipoprotein particles and address how TAG-rich lipoproteins are processed intracellularly. Understanding how macrophages take up and process different lipid species such as TAG is necessary to design future therapeutic interventions to correct excessive lipid accumulation and associated co-morbidities.
Topics: Triglycerides; Fatty Acids; Macrophages; Lipoproteins; Foam Cells; Lipoproteins, LDL
PubMed: 37619883
DOI: 10.1016/j.plipres.2023.101250 -
International Journal of Molecular... Nov 2022Neutrophil extracellular traps (NETs) are found in patients with various diseases, including cardiovascular diseases. We previously reported that copper-oxidized...
Neutrophil extracellular traps (NETs) are found in patients with various diseases, including cardiovascular diseases. We previously reported that copper-oxidized low-density lipoprotein (oxLDL) promotes NET formation of neutrophils, and that the resulting NETs increase the inflammatory responses of endothelial cells. In this study, we investigated the effects of high-density lipoproteins (HDL) on NET formation. HL-60-derived neutrophils were treated with phorbol 12-myristate 13-acetate (PMA) and further incubated with oxLDL and various concentrations of HDL for 2 h. NET formation was evaluated by quantifying extracellular DNA and myeloperoxidase. We found that the addition of native HDL partially decreased NET formation of neutrophils induced by oxLDL. This effect of HDL was lost when HDL was oxidized. We showed that oxidized phosphatidylcholines and lysophosphatidylcholine, which are generated in oxLDL, promoted NET formation of PMA-primed neutrophils, and NET formation by these products was completely blocked by native HDL. Furthermore, we found that an electronegative subfraction of LDL, LDL(-), which is separated from human plasma and is thought to be an in vivo oxLDL, was capable of promoting NET formation. These results suggest that plasma lipoproteins and their oxidative modifications play multiple roles in promoting NET formation, and that HDL acts as a suppressor of this response.
Topics: Humans; Lipoproteins, HDL; Extracellular Traps; Phospholipids; Endothelial Cells; Lipoproteins, LDL; Tetradecanoylphorbol Acetate
PubMed: 36430470
DOI: 10.3390/ijms232213992 -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405