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JAMA Cardiology Dec 2019The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles,... (Review)
Review
IMPORTANCE
The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles, chylomicron, and lipoprotein (a) particles in plasma is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. However, each of these particles contains one molecule of apolipoprotein B (apoB) and there is now substantial evidence that apoB more accurately measures the atherogenic risk owing to the apoB lipoproteins than does low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol.
OBSERVATIONS
Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic.
CONCLUSIONS AND RELEVANCE
Apolipoprotein B unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins.
Topics: Apolipoproteins B; Biomarkers; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, LDL; Cholesterol, VLDL; Coronary Artery Disease; Humans; Mendelian Randomization Analysis; Randomized Controlled Trials as Topic; Risk Assessment
PubMed: 31642874
DOI: 10.1001/jamacardio.2019.3780 -
Frontiers in Endocrinology 2020Elevations in plasma triglyceride are the result of overproduction and impaired clearance of triglyceride-rich lipoproteins-very low-density lipoproteins (VLDL) and... (Review)
Review
Elevations in plasma triglyceride are the result of overproduction and impaired clearance of triglyceride-rich lipoproteins-very low-density lipoproteins (VLDL) and chylomicrons. Hypertriglyceridemia is characterized by an accumulation in the circulation of large VLDL-VLDL-and its lipolytic products, and throughout the VLDL-LDL delipidation cascade perturbations occur that give rise to increased concentrations of remnant lipoproteins and small, dense low-density lipoprotein (LDL). The elevated risk of atherosclerotic cardiovascular disease in hypertriglyceridemia is believed to result from the exposure of the artery wall to these aberrant lipoprotein species. Key regulators of the metabolism of triglyceride-rich lipoproteins have been identified and a number of these are targets for pharmacological intervention. However, a clear picture is yet to emerge as to how to relate triglyceride lowering to reduced risk of atherosclerosis.
Topics: Cardiovascular Diseases; Humans; Hypertriglyceridemia; Triglycerides
PubMed: 32477261
DOI: 10.3389/fendo.2020.00252 -
Metabolites Oct 2021Apolipoprotein (apo) B, the critical structural protein of the atherogenic lipoproteins, has two major isoforms: apoB48 and apoB100. ApoB48 is found in chylomicrons and... (Review)
Review
Apolipoprotein (apo) B, the critical structural protein of the atherogenic lipoproteins, has two major isoforms: apoB48 and apoB100. ApoB48 is found in chylomicrons and chylomicron remnants with one apoB48 molecule per chylomicron particle. Similarly, a single apoB100 molecule is contained per particle of very-low-density lipoprotein (VLDL), intermediate density lipoprotein, LDL and lipoprotein(a). This unique one apoB per particle ratio makes plasma apoB concentration a direct measure of the number of circulating atherogenic lipoproteins. ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol content, which is variable. While LDL, the major cholesterol-carrying serum lipoprotein, is the primary therapeutic target for management and prevention of atherosclerotic cardiovascular disease, there is strong evidence that apoB is a more accurate indicator of cardiovascular risk than either total cholesterol or LDL cholesterol. This review examines multiple aspects of apoB structure and function, with a focus on the controversy over use of apoB as a therapeutic target in clinical practice. Ongoing coronary artery disease residual risk, despite lipid-lowering treatment, has left patients and clinicians with unsatisfactory options for monitoring cardiovascular health. At the present time, the substitution of apoB for LDL-C in cardiovascular disease prevention guidelines has been deemed unjustified, but discussions continue.
PubMed: 34677405
DOI: 10.3390/metabo11100690 -
Journal of the American Heart... Oct 2022In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than... (Review)
Review
Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk.
In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low-density lipoprotein, and low-density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low-density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL-C may obscure this relation. Next, the mechanisms that govern the number of very low-density lipoprotein and low-density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low-density lipoprotein and low-density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL-C or non-high-density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL-C and non-high-density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL-C or non-high-density lipoprotein cholesterol.
Topics: Humans; Cholesterol, LDL; Chylomicron Remnants; Cardiovascular Diseases; Risk Factors; Apolipoproteins B; Cholesterol; Lipoproteins; Biomarkers; Triglycerides; Heart Disease Risk Factors; Atherosclerosis; Lipoproteins, VLDL; Apolipoprotein B-100
PubMed: 36216435
DOI: 10.1161/JAHA.122.025858 -
Journal of Atherosclerosis and... Feb 2017Fasting hypertriglyceridemia is positively associated with the morbidity of coronary heart disease (CHD), and postprandial (non-fasting) hypertriglyceridemia is also... (Review)
Review
Fasting hypertriglyceridemia is positively associated with the morbidity of coronary heart disease (CHD), and postprandial (non-fasting) hypertriglyceridemia is also correlated with the risk status for CHD, which is related to the increase in chylomicron (CM) remnant lipoproteins produced from the intestine. CM remnant particles, as well as oxidized low density lipoprotein (LDL) or very low density lipoprotein (VLDL) remnants, are highly atherogenic and act by enhancing systemic inflammation, platelet activation, coagulation, thrombus formation, and macrophage foam cell formation. The cholesterol levels of remnant lipoproteins significantly correlate with small, dense LDL; impaired glucose tolerance (IGT) and CHD prevalence. We have developed an assay of apolipoprotein (apo)B-48 levels to evaluate the accumulation of CM remnants. Fasting apoB-48 levels correlate with the morbidity of postprandial hypertriglyceridemia, obesity, type III hyperlipoproteinemia, the metabolic syndrome, hypothyroidism, chronic kidney disease, and IGT. Fasting apoB-48 levels also correlate with carotid intima-media thickening and CHD prevalence, and a high apoB-48 level is a significant predictor of CHD risk, independent of the fasting TG level. Diet interventions, such as dietary fibers, polyphenols, medium-chain fatty acids, diacylglycerol, and long-chain n-3 polyunsaturated fatty acids (PUFA), ameliorate postprandial hypertriglyceridemia, moreover, drugs for dyslipidemia (n-3 PUFA, statins, fibrates or ezetimibe) and diabetes concerning incretins (dipeptidyl-peptidase IV inhibitor or glucagon like peptide-1 analogue) may improve postprandial hypertriglyceridemia. Since the accumulation of CM remnants correlates to impaired lipid and glucose metabolism and atherosclerotic cardiovascular events, further studies are required to investigate the characteristics, physiological activities, and functions of CM remnants for the development of new interventions to reduce atherogenicity.
Topics: Animals; Cholesterol; Humans; Hyperlipidemias; Lipoproteins; Postprandial Period; Triglycerides
PubMed: 27829582
DOI: 10.5551/jat.RV16003 -
Frontiers in Cardiovascular Medicine 2022This review aimed to summarize the evidence of elevated remnant cholesterol and the risks of atherosclerotic cardiovascular disease (ASCVD) and to search for further... (Review)
Review
This review aimed to summarize the evidence of elevated remnant cholesterol and the risks of atherosclerotic cardiovascular disease (ASCVD) and to search for further guidance in clinical therapy. The lipids-lowering treatments such as statins and ezetimibe targeted on low-density lipoprotein cholesterol (LDL-C) have always been the first-line therapy for ASCVD. However, even after statins or new lipid-lowering drugs lowered LDL-C to recommended concentrations, and with other risk factors well-controlled, such as high blood pressure, the risks of developing ASCVD remained. Remnant cholesterol (RC) referred to the cholesterol contained in all remnant lipoprotein particles, which was the cholesterol in the hydrolyzed very-low-density lipoprotein and intermediate-density lipoprotein in the fasting state, and the cholesterol in the chylomicron remnants in the postprandial state. Evidence from and animal pathogenic mechanisms studies, epidemiology, and genetic studies all indicated that RC played an important role in predicting the incidence of ASCVD. As a new indicator to reflect atherosclerosis, especially when LDL-C has been controlled to a recommended level, RC was considered as a priority treatment target for people at high risk of ASCVD. The use of statins, fibrates, APOC3 inhibitors, PCSK9 inhibitors, and omega-3 fatty acids to reduce RC levels in the plasma may provide long-term benefits. However, the standardized detection of RC was still controversial, and more studies on appropriate treatments of elevated RC are urgently needed. These positive trials may benefit more patients at high ASCVD risks worldwide in the future.
PubMed: 36324753
DOI: 10.3389/fcvm.2022.913869 -
Frontiers in Endocrinology 2020Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and... (Review)
Review
Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.
Topics: Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Insulin Resistance; Intestinal Mucosa; Intestines
PubMed: 32231641
DOI: 10.3389/fendo.2020.00116 -
Frontiers in Endocrinology 2022Bone is a highly dynamic tissue that undergoes continuous remodeling by bone resorbing osteoclasts and bone forming osteoblasts, a process regulated in large part by... (Review)
Review
Bone is a highly dynamic tissue that undergoes continuous remodeling by bone resorbing osteoclasts and bone forming osteoblasts, a process regulated in large part by osteocytes. Dysregulation of these coupled catabolic and anabolic processes as in the case of menopause, type 2 diabetes mellitus, anorexia nervosa, and chronic kidney disease is known to increase fracture risk. Recent advances in the field of bone cell metabolism and bioenergetics have revealed that maintenance of the skeleton places a high energy demand on these cells involved in bone remodeling. These new insights highlight the reason that bone tissue is the beneficiary of a substantial proportion of cardiac output and post-prandial chylomicron remnants and requires a rich supply of nutrients. Studies designed for the specific purpose of investigating the impact of dietary modifications on bone homeostasis or that alter diet composition and food intake to produce the model can be found throughout the literature; however, confounding dietary factors are often overlooked in some of the preclinical models. This review will examine some of the common pre-clinical models used to study skeletal biology and its pathologies and the subsequent impact of various dietary factors on these model systems. Furthermore, the review will include how inadvertent effects of some of these dietary components can influence bone cell function and study outcomes.
Topics: Bone Remodeling; Bone and Bones; Diabetes Mellitus, Type 2; Humans; Osteoclasts; Osteocytes
PubMed: 35909523
DOI: 10.3389/fendo.2022.932343