Recap and Lingering Questions
In part one of Beyond the Lipid Hypothesis, I covered the general process of plaque development, from the appearance of endogenous and exogenous pathogens, all the way up to plaque rupture and artery blockage. I studied this to truly examine the mechanisms and development of these fatty streaks and lesions that I had heard about growing up. Not to find root causes, as I had seen detailed in-depth by others (such as Ivor Cummins) over the past year, but to look at the tiniest pieces of the machine that make up atherosclerosis and truly understand how they fit together.
I had often heard about “foam cell formation” and “cholesterol in the arteries” but the explanations of why and, perhaps most interestingly, how this happens often left me in doubt or only with a vague understanding of how it allegedly works. As I continued to study foam cell formation and gained a greater understanding of the pathways for their development, I became increasingly curious as to the actual particles that contributed to foam cell formation, and the worsening of atherosclerosis.
A Familiar Particle
Based on the textbooks I had read and research I had done already, I knew that at least one type of “modified LDL” existed: oxidized LDL (oxLDL). However, I wasn’t quite sure why the LDL particles become oxidized.
One of the earlier hypotheses I had heard was that LDL somehow becomes lodged in the arterial wall and becomes oxidized as a consequence of exposure to the natural “environment” of the bloodstream. The theory proposes a similar, passive mechanism as leaving a shovel out in the yard resulting in rust to form. This example is easy to imagine and easy to understand given we’ve all left things out where the natural elements could get to them and cause problems. We don’t blame the environment, we blame ourselves for forgetting to bring it inside.
However, as explained in part one, what I found seemed to suggest the opposite sequence of events, namely oxidation of LDL occurs in circulation first and only afterward is it taken into the artery wall. What causes this to happen was still unclear to me up to this point. So to learn more about this process, I decided to focus on oxLDL first in the hopes of gaining a better understanding of the immune response involved in atherosclerosis as a whole.
What I discovered was that LDL can be oxidized in a wide variety of ways, and can include oxidation of the phospholipid shell, oxidation of Apolipoprotein B on the LDL particle1, as well as oxidation of the cholesterol and triglycerides inside of it.2 The oxidation of the cholesterol carried by LDL results in the formation of oxysterol which can be found in many atherosclerotic lesions3 and excess accumulation of which contributes to macrophage death4, 5. Which, as explained in Part 1 of this series, is a contributor to plaque destabilization.
Frustratingly, I found that oxidized LDL was usually described in terms of how it interacts with different parts of the system, such as the interaction with scavenger receptors and macrophages, rather than how it was actually oxidized. Generally, a study regarding oxLDL uptake was referring to LDL oxidized in laboratory conditions, instead of how it would be oxidized in vivo (in the body). In an attempt to find real-world causes of LDL oxidation, I decided to look more into how LDL could be oxidized under “natural” conditions that may occur in the life of the everyday person.
A Balancing Act
One example of LDL being oxidized in a “real life” situation, outside of laboratory conditions, was exposure to reactive oxygen species and reactive nitrogen species6. The terms free radical, reactive oxygen species (ROS), and reactive nitrogen species (RNS) refer to entire classes of particles that come in many forms. Their key feature is that they have at least one free electron and thus can “steal” an atom from another particle. In the case of lipoprotein oxidation, hydrogen is taken from some of the lipid (fat) that forms the phospholipid shell of the LDL particle.7 The free space left by the stolen hydrogen is then filled by an oxygen molecule on the recipient particle and thus becomes “oxidized”.8 This oxidized LDL is damaged or altered, in such a way that it is no longer recognizable by LDL receptors and thus must be cleared via alternate pathways.
Free radicals aren’t solely a villain in their role, however, and can be produced for or from beneficial purposes like cellular signalling mechanisms9, and as a defensive and signalling tool produced by macrophages and other cells in reaction to bacteria and other pathogens10, 11, 12, as well as produced by muscle cells especially during exercise13. Like many things, it appears that it is not the presence of free radicals in itself that is deleterious but rather the overwhelming of normal neutralization methods wherein it becomes dysfunctional and can lead to disease14.
Considering the signaling and defense uses, endogenous production of ROS (production in and by the body), may be unavoidable but moderate levels present in normal circumstances appear to be beneficial if not necessary for normal function15. I found that there are many uses for this potentially destructive class of particle, and as is true for most things in the body, it is hard to classify as “good” or “bad”. Rather, these particles must be looked at in the context of their necessary function, as well as the potential unbalancing that can occur within the system.
Infection and Oxidative Stress
The destruction comes when this unbalancing occurs resulting in a shift towards a free radical dominant environment and depletion of antioxidants which help neutralize reactive oxygen species. This state is called oxidative stress16 and can cause OxLDL17, resulting in foam cell formation and worsening of atherosclerosis if chronic and severe enough, and the death of cells (such as smooth muscle cells in the arteries)18. I also found that infections, both viral19 and bacterial20, can also cause oxidative stress as a result of the production of Reactive Oxygen Species and Reactive Nitrogen Species21, and this too can manifest harmful effects under the right conditions. Not only that, but this damaging effect of chronic or highly acute oxidative stress mediated by infection has been shown to contribute to the development of cardiovascular disease in some animal models22 and the possibility of the same in human in vitro (laboratory settings working with isolated tissue) studies23 and very preliminary data involving infections of chlamydia pneumonia (C. Pneumonia)24 and cytomegalovirus25.
The increase in risk in human models may, however, be partially due to the direct contribution of the particle clearance pathways involved in the development of plaque mentioned in Part 1. Among these direct contributions are LOX-1 (a scavenger receptor that recognizes oxLDL and other pathogenic particles) being able to take in C. Pneumoniae, directly26, as well as both enhancing expression of scavenger receptors27, 28, and an increased uptake of oxLDL by macrophages29, 30. Meaning that C. Pneumonia and Cytomegalovirus appears to contribute directly, through the aforementioned mechanisms, as well as peripherally31 (e.g. via oxidative stress, and oxidation of LDL), to the overwhelming of the immune response pathways involved in the development of atherosclerotic plaque.
Beyond contributions of oxidation from responses to defense and signaling there also exist outside sources of free radicals that can contribute to oxidative stress inside the body. The most common example I found was smoking32, 33, along with exposure to radiation34, 35 and air pollution36. The mechanistic link between smoking and heart disease had never been clear to me before, until I understood that smoking increases the oxidative stress in the body via free radical introduction, and ultimately increases the amount of damaged LDL in the system that must be cleared. Various other dietary factors also appeared to increase oxidative stress and LDL modification including high intake of Polyunsaturated Fatty Acid (PUFA) such as those found in seed oils37,as well as high refined carbohydrate intake38, 39.
A Little Different
Additionally, I found that certain types, or classes, of LDL are more easily oxidized and production of these types increases during an inflammatory response. After digging further, I came across multiple studies referring to an increase in the production of VLDL (the initial stage of LDL)40 during inflammation41, mediated by pro-inflammatory cytokines – signalling molecules that help promote inflammation – in mouse studies42, 43, and emerging evidence for a similar reaction in humans44. This reaction, demonstrated by in vitro mouse studies, results in hypertriglyceridemia(45) (increased levels of triglycerides) which, in other studies, appears to lead to the increase in “small, dense” LDL (sdLDL)46, 47. We can additionally see this same lipoprotein profile in humans with inflammatory conditions as well48, and sdLDL has been demonstrated to be far more prone to modification49, 50. I was quite curious as to the cause of this vulnerability to oxidation, as it did not make sense to me why two different types of LDL would be more or less prone to damage just based on size alone.
I found that there appeared to be several factors in this vulnerability, and that it has been speculated that the protein content and structure of the sdLDL may increase the exposure of the polyunsaturated fatty acids that contribute to the structure of its phospholipid shell – increasing sdLDL’s vulnerability to oxidation.51 These structural differences leads to a difference in ‘lag time’ – a term which refers to the amount of time it takes for LDL to deplete of antioxidants before the LDL particle itself is subject to oxidation.52 Not only that, but the PUFA content of this type of LDL is also higher than the “light, fluffy” LDL we typically see that is used for energy transportation throughout the body.53 Clearly the oxidative susceptibility of small dense LDL is not a simple process, but rather a multifactorial one involving many different aspects of the physiological structure and composition of the particle, all appearing to lend itself to quicker donation of antioxidants, and a faster rate and deeper level of oxidative modification to the particle.
Not So Sweet
Beyond oxidated LDL, I found that there was an additional type of modified LDL called glycated LDL54. Glycation refers to damage of a particle caused by glucose binding to a protein or lipid molecule on said particle – a sticky candy coating that damages the particle (like LDL or a red blood cell). Before discovering this, I was already familiar with a different type of glycation involving hemoglobin, or red blood cells, which is measured via Hemoglobin A1c (HbA1c). HbA1c can go up in the case of high blood sugar, as seen in cases of advanced diabetes, as does glycation of LDL particles. Some amount of LDL glycation occurs in the healthy system, as is also true of glycation of hemoglobin, but higher levels of glycated LDL may cascade into further problems down the road. Not only is glycated LDL a form of modified LDL which is recognized by scavenger receptors55, but higher levels of this glycated LDL may lead to higher levels of oxidated LDL, as well. According to the research I read on the topic, the process of glucose damaging both apolipoprotein B and the phospholipid shell leaves the LDL particle more at risk of oxidation. This appears to be due to this modification crippling the usage of antioxidants, like vitamin E, in the LDL particle during this so-called “glycation phase”. As a result, this shortens the lag time in the particle and speeds up the accumulation of damage from oxidation56. This creates not only a glycated LDL particle, but a glycoxidized one yet again resulting in increased dependence on clearance pathways previously discussed – contributing to an overwhelming of clearance mechanisms and detrimental development of atherosclerosis over time if the cause of the damage is chronic.
It became evident that there are two major factors to the level of oxidation of LDL that contribute to this chronic “high alert” of damage and inflammation. Perhaps the most obvious factor is a source of oxidation. In order for LDL to become oxidized, there must first be an increase in oxidative particles (Reactive Oxygen Species, for example) severe (or chronic) enough to deplete the system of available antioxidants within the body (e.g. oxidative stress). LDL normally carry fat soluble vitamins as part of their “cargo” and if they come across reactive oxygen species, they can use these antioxidants to safely neutralize them and get away unscathed. The depletion of the antioxidants carried by LDL (this can be thought of as LDL running out of ammo) is what causes the lag time between oxidative agents being introduced, and LDL actually becoming oxidized and damaged. Thus, in order for there to be wide-scale oxidation of LDL, there must also be a wide-scale presence of oxidative stress as well, if the logic holds. The source of this oxidative stress can come from many different sources, only a few of which are covered by this post.
The second important factor to LDL oxidation is the susceptibility of the LDL particles to become damaged by it, as opposed to merely using up its antioxidant “ammo” as a preservative measure without taking any damage from the encounter. Before I truly delved deeply into the topic I thought that low density lipoproteins were the same when it came to oxidative susceptibility. However, this does not appear be true. Not only is LDL that has been damaged by glycation more susceptible to oxidation, due to the damage done to it, but small dense LDL likewise is more susceptible to oxidative damage far more than its so-called “large, fluffy” counterpart. This susceptibility isn’t because small dense is “damaged”, at least as far as I am aware, but rather that the physical structure makes it more vulnerable. The mere fact that there are LDL particles that are more quickly and thoroughly oxidized that appear ‘on scene’ during oxidative stress and inflammation is an interesting prospect that leaves me with more questions than I had before I had discovered this aspect of LDL
Shared Causes and Conclusion
If one wants to understand what increases the formation of foam cells (which also worsens atherosclerosis along the way) over the course of years, one must look at the type of LDL particles that contribute to them (modified LDL) and what causes the modification of LDL in the first place. Very quickly I learned that the topic of LDL oxidation, and modification, is a deeply complicated one. This post, by no means, covers all factors of LDL modification but at the very least I began to better understand it. I began to notice that the more chronic sources of oxLDL tended to mirror Ivor Cummins graph of contributing factors to chronic disease. This does seem to point to shared mechanisms, and shared root causes, of heart disease and insulin resistance as he has suggested previously. The role of insulin in heart disease is where I will explore next, in part 3 of Beyond the Lipid Hypothesis to see what hints lie in insulin’s contribution to the disease on a mechanistic level.
1Levitan, Irena, Suncica Volkov, and Papasani V. Subbaiah. “Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology.” Antioxidants & Redox Signaling 13.1 (2010): 39–75. PMC. Web. 26 Oct. 2017. doi:10.1089/ars.2009.2733
2Patel, Rakesh P., et al. “Formation of Oxysterols during Oxidation of Low Density Lipoprotein by Peroxynitrite, Myoglobin, and Copper.” Journal of Lipid Research, Nov. 1996, PMID: 8978488
3Garcia-Cruset, Sandra, et al. “Oxysterol profiles of normal human arteries, fatty streaks and advanced lesions” Taylor and Francis Online, 1 June 1999, doi:10.1080/10715760100300571
4Clare, K, et al. “Toxicity of Oxysterols to Human Monocyte-Macrophages.” Atherosclerosis., U.S. National Library of Medicine, Nov. 1995, PMID:8579633
5Ward, Liam J. et al. “Exposure to Atheroma-Relevant 7-Oxysterols Causes Proteomic Alterations in Cell Death, Cellular Longevity, and Lipid Metabolism in THP-1 Macrophages.” Ed. Ivano Eberini. PLoS ONE 12.3 (2017): e0174475. PMC. Web. 27 Oct. 2017. doi:10.1371/journal.pone.0174475
6Carr, Anitra C., et al. Oxidation of LDL by Myeloperoxidase and Reactive Nitrogen Species. Arteriosclerosis, Thrombosis, and Vascular Biology, 1 July 2000, doi:10.1161/01.ATV.20.7.1716
7Aruoma, Okezie I. Free Radicals, Oxidative Stress, and Antioxidants in Human Health and Disease. Journal of the American Oil Chemists’ Society, Feb. 1998, doi:10.1007/s11746-998-0032-9.
8Jialal, I, and S Devaraj. “Low-density lipoprotein oxidation, antioxidants, and atherosclerosis: a clinical biochemistry perspective..” Clinical Chemistry 42.4 (1996): 498-506. Web. 26 Oct. 2017. PMID:8605665
9D’Autréaux, Benoît, and Michel B. Toledano. ROS as Signalling Molecules Mechanisms That Generate Specificity in ROS Homeostasis. Nature Reviews Molecular Cell Biology, Oct. 2007, doi:10.1038/nrm2256.
10Fang, Ferric C. Antimicrobial Reactive Oxygen and Nitrogen Species: Concepts and Controversies. Nature Reviews Microbiology, 1 Oct. 2004, doi:10.1038/nrmicro1004.
11Forman, Henry Jay, and Martine Torres. Reactive Oxygen Species and Cell Signaling Respiratory Burst in Macrophage Signaling. American Journal of Respiratory and Critical Care Medicine, 1 Oct. 2002, doi:10.1164/rccm.2206007
12Gwinn, Maureen R., and Val Vallyathan. Respiratory Burst: Role in Signal Transduction in Alveolar Macrophages. Journal of Toxicology and Environmental Health, 24 Feb. 2007, doi:10.1080/15287390500196081.
13Powers, Scott K., and Malcolm J. Jackson. “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production.” Physiological reviews 88.4 (2008): 1243–1276. PMC. Web. 27 Oct. 2017. doi:10.1152/physrev.00031.2007
14Poljsak, Borut, et al. “Achieving the Balance between ROS and Antioxidants When to Use the Synthetic Antioxidants.” Oxidative Medicine and Cellular Longevity, 4 Feb. 2013, doi:10.1155/2013/956792.
15Dröge, Wulf. “Free Radicals in the Physiological Control of Cell Function.” Physiological Reviews, 1 Jan. 2002, doi:10.1152/physrev.00018.2001
16Burton, Graham J., and Eric Jauniaux. “Oxidative Stress.” Best Practice & Research. Clinical Obstetrics & Gynaecology 25.3 (2011): 287–299. PMC. Web. 27 Oct. 2017. doi:10.1016/j.bpobgyn.2010.10.016
17Itabe, Hiroyuki. “Oxidized Low-Density Lipoprotein as a Biomarker of in Vivo Oxidative Stress: From Atherosclerosis to Periodontitis.” Journal of Clinical Biochemistry and Nutrition 51.1 (2012): 1–8. PMC. Web. 27 Oct. 2017. doi:10.3164/jcbn.11-00020R1
18Zhang, Chao et al. “Poly(ADP-Ribose) Protects Vascular Smooth Muscle Cells from Oxidative DNA Damage.” BMB Reports 48.6 (2015): 354–359. PMC. Web. 27 Oct. 2017. doi:10.5483/BMBRep.2015.48.6.012
19Schwarz, Kathleen B. “Oxidative Stress during Viral Infection: A Review.” Free Radical Biology and Medicine, 1996, doi:10.1016/0891-5849(96)00131-1.
20Ding, Song-Ze et al. “Helicobacter Pylori Infection Induces Oxidative Stress and Programmed Cell Death in Human Gastric Epithelial Cells .” Infection and Immunity 75.8 (2007): 4030–4039. PMC. Web. 27 Oct. 2017. doi:10.1128/IAI.00172-07
21Ivanov, Alexander V., et al. Oxidative Stress in Infection and Consequent Disease. Oxidative Medicine and Cellular Longevity, Jan. 2017, doi:10.1155/2017/3496043.
22Ostos, Maria A, et al. Implication of Natural Killer T Cells in Atherosclerosis Development during a LPS-Induced Chronic Inflammation. FEBS Letters, 19 Apr. 2002, doi:10.1016/S0014-5793(02)02692-3.
23Wang, Jun et al. “Lipopolysaccharide Promotes Lipid Accumulation in Human Adventitial Fibroblasts via TLR4-NF-κB Pathway.” Lipids in Health and Disease 11 (2012): 139. PMC. Web. 27 Oct. 2017. doi:10.1186/1476-511X-11-139
24Watson, Caroline, and Nicholas J. Alp. Role of Chlamydia Pneumoniae in Atherosclerosis. Clinical Science, 1 Apr. 2008, doi:10.1042/CS20070298
25Izadi, Morteza et al. “Cytomegalovirus Localization in Atherosclerotic Plaques Is Associated with Acute Coronary Syndromes: Report of 105 Patients.” Methodist DeBakey Cardiovascular Journal 8.2 (2012): 42–46. Print.
26Campbell, Lee Ann et al. “Chlamydia Pneumoniae Binds to the Lectin-like Oxidized LDL Receptor for Infection of Endothelial Cells.” Microbes and infection / Institut Pasteur 14.1 (2012): 43–49. PMC. Web. 27 Oct. 2017. doi:10.1016/j.micinf.2011.08.003
27Campbell, Lee Ann et al. “Chlamydia Pneumoniae Induces Expression of Proatherogenic Factors through Activation of the Lectin-like Oxidized LDL Receptor-1.” Pathogens and disease 69.1 (2013): 1–6. PMC. Web. 27 Oct. 2017. doi:10.1111/2049-632X.12058
28Zhou, Y F et al. “Human Cytomegalovirus Increases Modified Low Density Lipoprotein Uptake and Scavenger Receptor mRNA Expression in Vascular Smooth Muscle Cells.” Journal of Clinical Investigation 98.9 (1996): 2129–2138. Print. doi:10.1172/JCI119019
29MV, Kalayoglu, et al. “Characterization of Low-Density Lipoprotein Uptake by Murine Macrophages Exposed to Chlamydia Pneumoniae.” Microbes and Infection, 1 May 1999, doi:10.1016/S1286-4579(99)80044-6.
30Carlquist, John F., et al. “Cytomegalovirus Stimulated MRNA Accumulation and Cell Surface Expression of the Oxidized LDL Scavenger Receptor, CD36.” Atherosclerosis, Nov. 2004, doi:10.1016/j.atherosclerosis.2004.07.010.
31Kalayoglu, Murat V., et al. “Cellular Oxidation of Low-Density Lipoprotein by Chlamydia Pneumoniae.” The Journal of Infectious Diseases, 1 Sept. 1999, doi:10.1086/314931.
32Isik, Birgul, et al. Oxidative Stress in Smokers and Non-Smokers. Inhalation Toxicology, 15 Nov. 2006, doi:10.1080/08958370701401418.
33Ozguner, Fehmi, et al. Active Smoking Causes Oxidative Stress and Decreases Blood Melatonin Levels. Toxicology and Industrial Health, 1 Nov. 2005, doi:10.1191/0748233705th211oa.
34Azzam, Edouard I., Jean-Paul Jay-Gerin, and Debkumar Pain. “Ionizing Radiation-Induced Metabolic Oxidative Stress and Prolonged Cell Injury.” Cancer letters 327.0 (2012): 48–60. PMC. Web. 27 Oct. 2017. doi:10.1016/j.canlet.2011.12.012
35Einor, D., et al. Onizing Radiation, Antioxidant Response and Oxidative Damage: A Meta-Analysis. Science of the Total Environment, 1 Apr. 2016, doi:10.1016/j.scitotenv.2016.01.027.
36Lodovici, Maura, and Elisabetta Bigagli. “Oxidative Stress and Air Pollution Exposure.” Journal of Toxicology 2011 (2011): 487074. PMC. Web. 27 Oct. 2017. doi:10.1155/2011/487074
37Mata, P., et al. Effect of Dietary Fat Saturation on LDL Oxidation and Monocyte Adhesion to Human Endothelial Cells in Vitro. Arteriosclerosis, Thrombosis, and Vascular Biology., 1 Nov. 1996, doi:10.1161/01.ATV.16.11.1347
38Guay, Valérie, et al. Effect of Short-Term Low- and High-Fat Diets on Low-Density Lipoprotein Particle Size in Normolipidemic Subjects. Metabolism Clinical and Experimental, Jan. 2012, doi:10.1016/j.metabol.2011.06.002.
39Siri, Patty W., and Ronald M. Krauss. Influence of Dietary Carbohydrate and Fat on LDL and HDL Particle Distributions. Current Atherosclerosis Reports, Nov. 2005.
40Khovidhunkit, Weerapan, et al. “Infection and Inflammation-Induced Proatherogenic Changes of Lipoproteins.” The Journal of Infectious Diseases, 1 June 2000, doi:10.1086/315611.
41Aspichueta, Patricia, et al. Disrupted VLDL Features and Lipoprotein Metabolism in Sepsis. INTECH.
42Bartolomé, Nerea, et al. “Biphasic Adaptative Responses in VLDL Metabolism and Lipoprotein Homeostasis during Gram-Negative Endotoxemia.” Innate Immunity, 26 Nov. 2010, doi:10.1177/1753425910390722.
43Aspichueta, Patricia, et al. “Endotoxin Promotes Preferential Periportal Upregulation of VLDL Secretion in the Rat Liver.” Journal of Lipid Research, 4 Jan. 2005, doi:10.1194/jlr.M500003-JLR200.
44Starnes, H F et al. “Tumor Necrosis Factor and the Acute Metabolic Response to Tissue Injury in Man.” Journal of Clinical Investigation 82.4 (1988): 1321–1325. Print. doi:10.1172/JCI113733
45Grunfeld, Carl, and Kenneth R. Feingold. Tumor Necrosis Factor, Cytokines, and the Hyperlipidemia of Infection. Trends in Endocrinology & Metabolism, 1991, doi:10.1016/1043-2760(91)90027-K.
46Ivanova, Ekaterina A., et al. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxidative Medicine and Cellular Longevity, 2017, doi:10.1155/2017/1273042.
47Hirayama, Satoshi, and Takashi Miida. Small Dense LDL: An Emerging Risk Factor for Cardiovascular Disease. Clinica Chimica Acta, 24 Dec. 2012. doi:10.1016/j.cca.2012.09.010
48Feingold, Kenneth R., and Carl Grunfeld. The Effect of Inflammation and Infection on Lipids and Lipoproteins. Endotext, 12 June 2015.
49Chait, Alan, et al. Susceptibility of Small, Dense, Low-Density Lipoproteins to Oxidative Modification in Subjects with the Atherogenic Lipoprotein Phenotype, Pattern B. The American Journal of Medicine, Apr. 1993, doi:10.1016/0002-9343(93)90144-E.
50Soran, Handrean, and Paul N. Durrington. Susceptibility of LDL and Its Subfractions to Glycation. Current Opinion in Lipidology, Aug. 2011, doi:10.1097/MOL.0b013e328348a43f.
51Ohmura, Hirotoshi, et al. Lipid Compositional Differences of Small, Dense Low-Density Lipoprotein Particle Influence Its Oxidative Susceptibility. Metabolism Clinical and Experimental, Sept. 2002, doi:10.1053/meta.2002.34695.
52Tribble, Diane L., et al. Greater Oxidative Susceptibility of the Surface Monolayer in Small Dense LDL May Contribute to Differences in Copper-Induced Oxidation among LDL Density Subfractions. Journal of Lipid Research, Apr. 1995.
53De Graaf, J, et al. Enhanced Susceptibility to In Vitro Oxidation of the Dense Low Density Lipoprotein Subfraction in Healthy Subjects. Arteriosclerosis, Thrombosis, and Vascular Biology., 1 Mar. 1991, doi:10.1161/01.ATV.11.2.298
54Younis, Nahla, et al. Glycation as an Atherogenic Modification of LDL. Current Opinion on Lipidology, Aug. 2008, doi:10.1097/MOL.0b013e328306a057.
55Lam, Michael C.W., et al. Glycoxidized Low-Density Lipoprotein Regulates the Expression of Scavenger Receptors in THP-1 Macrophages. Atherosclerosis, Dec. 2004, doi:10.1016/j.atherosclerosis.2004.08.003.
56Sobal, G., et al. Why Is Glycated LDL More Sensitive to Oxidation than Native LDL? A Comparative Study. PLEFA, Oct. 2000, doi:10.1054/plef.2000.0204.