The Problematic Paradigm of LDL-C, Part 9

Part 9 - An Energy Delivery Model: The Downstream Consequences of an Impaired Energy Delivery System

Previous - Part 8 - An Energy Delivery Model: The Contrasting Presentations of Elevated LDL-C

Over the preceding sections, we’ve driven home a few important facts:

• There is effectively no independent relationship between LDL cholesterol and cardiovascular outcomes
• There are two major manners by which the energy delivery nature of lipid metabolism can lead to elevated LDL cholesterol

The word “independent” is emphasized because without considering factors of metabolic health, the relationship between elevated LDL-C and poor cardiovascular outcomes does exist. But it appears to exist only because the number of people with elevated LDL-C through poor metabolic health (poor triglyceride utilization, increased triglyceride return to the liver, etc.) dwarf the number of people whose LDL-C is elevated as a result of an increased demand for efficient energy delivery. Because LDL-C is far more commonly elevated in unhealthy individuals, the relationship between LDL-C and cardiovascular disease persists and cholesterol appears to be a possible culprit. But is elevated LDL-C the reason for the disease, or does it simply occur alongside the real disease process? Let’s dive in –

 

Increased Triglyceride Return to the Liver

As you’ll recall, poor triglyceride uptake at the periphery results in an extended VLDL lifespan and a preponderance of triglyceride-rich lipoproteins. These lipoproteins must offload some of their excess triglyceride burden, and do so via the CETP-mediated exchange of triglycerides to HDL and LDL particles. This “spreads out” the excess triglycerides for return to the liver.

This exchange is the reason for depressed HDL-C in metabolically unhealthy persons, but it’s the effect on LDL particles on which we’ll focus. When an LDL particle serves as the trade partner, it gives away some amount of cholesterol to the VLDL and takes on a corresponding triglyceride load. Now, both particles return to the liver to offload much of their triglyceride burden there.

This process is aided by an increased expression of the LDL receptor and increased activity of an enzyme known as hepatic lipase.^1–5 Typically, the principal role of hepatic lipase is to remove triglycerides and remodel the VLDL remnants to LDL particles, such that they may reenter the bloodstream. However in this case, because LDL particles are unusually rich in triglycerides, they too will be acted upon by hepatic lipase for triglyceride removal. While these particles didn’t change in size when they traded away cholesterol for triglycerides, they now shrink with the removal of those excess triglycerides.^5–8

 

Impact of Modified LDL Particles

Herein lies one of the major ways in which poor metabolic efficiency can elevate one’s risk for cardiovascular disease. Small, dense LDL particles (sdLDL) are significantly more prone to undesirable modification than are normal LDL particles.^9–14 This vulnerability is one of the reasons individuals with poor metabolic health, and thus more sdLDL, also have higher levels of oxidized and glycated LDL particles that ultimately help trigger an immune response (although, as we will see in a later section, diet can also lead to modification of normal sized LDL particles as well).^12–18   

Glycated and oxidized LDL particles are those that have been damaged by exposure to elevated blood sugar and oxidative stress, respectively. They, along with yet undamaged sdLDL, are collectively known as “modified LDL particles,” and are instrumental in the genesis of cardiovascular disease. These particles are the preferential target of receptors such as lectin-type oxidized LDL receptor 1, or LOX-1, which serves to bind and degrade modified LDL particles in the lining of the blood vessel.^19,20 LOX-1 activity is typically quite low, but is increased in the presence of elevated blood sugar, oxidized LDL particles, and certain inflammatory mediators.^21–27

LOX-1 acts by binding and engulfing the modified LDL particle in the vessel wall, which has multiple cascading effects. These include:

•  Increased expression of NADPH Oxidase, an often-dormant enzyme that catalyzes the formation of reactive oxygen species (“free radicals”)^28,29
•  Increased expression of the immune-modulating protein NF-kB, which plays an inflammatory role in many disease states^30–32
• Increased action, via NF-kB, of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein 1 (MCP1), which aid in the signaling of immune cells to the site of the vessel-bound LDL particle^19,33–35

 

Before continuing, this is a good time to stress again that the cholesterol contained within these molecules has nothing to do with this process, and that unmodified LDL particles are not a normal target for LOX-1 binding.^19,36–39

 

Immune Activity

So what happens after LOX-1 binds a modified LDL particle and begins signaling other molecules to get involved? One main effect is the aforementioned upregulation of adhesion molecules such as VCAM1 and MCP1, which generally serve to attract and mediate the adhesion of immune cells known as macrophages to the areas of LDL particle entrapment. These macrophages can then move into the wall of the blood vessel and internalize the LDL particle, which are degraded during the formation of something known as a foam cell.^40–42

Foam cells can broadly take two paths from here. The first involves the transport of the free cholesterol from the now-degraded LDL particle to the surface of the foam cell for eventual recycling to the body.⁴³ Consider this entire process from an evolutionary perspective to understand why this is natural and likely helpful – Even in a very healthy person, some LDL particles are inevitably going to be modified or damaged, making them a target of LOX-1 and a subsequent immune response. While it might sound crazy in the context of plaque and modern heart disease, the binding of a damaged particle to the wall of the blood vessel serves an important purpose – it prevents the damaged LDL from traveling to other parts of the body and furthering oxidative damage elsewhere. With the aforementioned systems in place to capture, destroy, and recycle its components, the occasional damaged LDL particle can be sequestered and then removed from the blood vessel with no long-term damage or risk.

The second path, however, is far more sinister and may be followed when the rate of damaged particle entrapment exceeds the rate of particle removal. Foam cells themselves release macrophage retention factors that discourage migration away from the initial site of LDL entrapment and encourage further macrophage activity.^42,44,45 This promotes the proliferation of something called vascular smooth muscle cells (VSMC), the cells that form the wall of the blood vessel. Particularly in cases of significant foam cell formation, these VSMCs will help form a fibrous cap (a new vessel wall, essentially) over the site of LDL and macrophage accumulation. This blocks off the foam cells from the rest of the bloodstream, but also narrows the blood vessel itself. The progressive thickening and potential rupture of these VSMC caps are what lead to arterial blockage and other cardiovascular manifestation of disease.^46–49

Of note – the VSMC cap interferes with normal calcium regulation and encourages calcium depositions in the blood vessels that can be measured on a coronary artery calcium (CAC) scan.^50–52 A CAC scan is one of the gold standard measures of potential heart disease, as it measures narrowing and potential blockages in the vessels themselves. It is when following this second path – when the immune response to modified LDL particles exceeds the capacity to clear them – that calcium deposits are noted and significant arterial narrowing may occur.

The genesis of sdLDL is instrumental in the formation of arterial plaques and the progression of cardiovascular disease. However, it is not the only factor that increases the risk for cardiovascular events. As noted, the glycation and oxidation of normal LDL particles can contribute as well, as can a variety of other factors that we will explore in the next section.

 

**Key Takeaways

• The increase in triglyceride return to the liver results in an increased action of hepatic lipase on LDL particles, causing them to shrink in size
• sdLDL particles are particularly prone to oxidative and glycemic damage and, along with other damaged LDL particles, may be bound in the vessel wall by receptors such as LOX-1
• The binding of a modified LDL particle by LOX-1 triggers an immune response at the site of LDL entrapment, resulting in the formation of macrophage foam cells
• When the rate of foam cell and VSMC cap formation exceeds the capacity to degrade and recycle the damaged LDL particles, plaques can occur

Part 10 - Other Factors in the Development of Atherosclerosis

 

 

1.               Streicher R, Kotzka J, Müller-Wieland D, et al. SREBP-1 mediates activation of the low density lipoprotein receptor promoter by insulin and insulin-like growth factor-I. J Biol Chem. 1996;271(12):7128-7133. doi:10.1074/jbc.271.12.7128

2.               Salter AM, Fisher SC, Brindley DN. Binding of low-density lipoprotein to monolayer cultures of rat hepatocytes is increased by insulin and decreased by dexamethasone. FEBS Lett. 1987;220(1):159-162. doi:10.1016/0014-5793(87)80895-5

3.               Au DT, Strickland DK, Muratoglu SC. The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling. J Diabetes Res. 2017;2017:8356537. doi:10.1155/2017/8356537

4.               Rashid S, Watanabe T, Sakaue T, Lewis GF. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem. 2003;36(6):421-429. doi:10.1016/s0009-9120(03)00078-x

5.               Kobayashi J, Miyashita K, Nakajima K, Mabuchi H. Hepatic Lipase: a Comprehensive View of its Role on Plasma Lipid and Lipoprotein Metabolism. J Atheroscler Thromb. 2015;22(10):1001-1011. doi:10.5551/jat.31617

6.               Jansen H, Verhoeven AJM, Sijbrands EJG. Hepatic lipase. Journal of Lipid Research. 2002;43(9):1352-1362. doi:10.1194/jlr.R200008-JLR200

7.               Brunzell JD, Zambon A, Deeb SS. The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2012;1821(3):365-372. doi:10.1016/j.bbalip.2011.09.008

8.               Zambon A, Austin MA, Brown BG, Hokanson JE, Brunzell JD. Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology. 1993;13(2):147-153. doi:10.1161/01.ATV.13.2.147

9.               Hurt-Camejo E, Camejo G, Rosengren B, et al. Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology. 1992;12(5):569-583. doi:10.1161/01.ATV.12.5.569

10.             Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. The American Journal of Medicine. 1993;94(4):350-356. doi:10.1016/0002-9343(93)90144-E

11.             Sobal G, Menzel J, Sinzinger H. Why is glycated LDL more sensitive to oxidation than native LDL? A comparative study. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2000;63(4):177-186. doi:10.1054/plef.2000.0204

12.             Soran H, Durrington PN. Susceptibility of LDL and its subfractions to glycation. Curr Opin Lipidol. 2011;22(4):254-261. doi:10.1097/MOL.0b013e328348a43f

13.             Younis N, Charlton-Menys V, Sharma R, Soran H, Durrington PN. Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro. Atherosclerosis. 2009;202(1):162-168. doi:10.1016/j.atherosclerosis.2008.04.036

14.             Younis NN, Soran H, Sharma R, et al. Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes: Diabetes and Vascular Disease Research. Published online September 27, 2010. doi:10.1177/1479164110383063

15.             Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR. Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA. 2008;299(19):2287-2293. doi:10.1001/jama.299.19.2287

16.             Holvoet P, Kritchevsky SB, Tracy RP, et al. The Metabolic Syndrome, Circulating Oxidized LDL, and Risk of Myocardial Infarction in Well-Functioning Elderly People in the Health, Aging, and Body Composition Cohort. Diabetes. 2004;53(4):1068-1073. doi:10.2337/diabetes.53.4.1068

17.             Sigurdardottir V, Fagerberg B, Hulthe J. Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study). Journal of Internal Medicine. 2002;252(5):440-447. doi:10.1046/j.1365-2796.2002.01054.x

18.             Lapointe A, Couillard C, Piché MÈ, et al. Circulating oxidized LDL is associated with parameters of the metabolic syndrome in postmenopausal women. Atherosclerosis. 2007;191(2):362-368. doi:10.1016/j.atherosclerosis.2006.03.036

19.             Twigg MW, Freestone K, Homer-Vanniasinkam S, Ponnambalam S. The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease. Cardiology Research and Practice. 2012;2012:e632408. doi:10.1155/2012/632408

20.             Sawamura T, Wakabayashi I, Okamura T. LOX-1 in atherosclerotic disease. Clinica Chimica Acta. 2015;440:157-163. doi:10.1016/j.cca.2014.11.016

21.             Chen M, Nagase M, Fujita T, Narumiya S, Masaki T, Sawamura T. Diabetes Enhances Lectin-like Oxidized LDL Receptor-1 (LOX-1) Expression in the Vascular Endothelium: Possible Role of LOX-1 Ligand and AGE. Biochemical and Biophysical Research Communications. 2001;287(4):962-968. doi:10.1006/bbrc.2001.5674

22.             Li L, Sawamura T, Renier G. Glucose Enhances Endothelial LOX-1 Expression: Role for LOX-1 in Glucose-Induced Human Monocyte Adhesion to Endothelium. Diabetes. 2003;52(7):1843-1850. doi:10.2337/diabetes.52.7.1843

23.             Hofnagel O, Luechtenborg B, Stolle K, et al. Proinflammatory cytokines regulate LOX-1 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24(10):1789-1795. doi:10.1161/01.ATV.0000140061.89096.2b

24.             Kattoor AJ, Goel A, Mehta JL. LOX-1: Regulation, Signaling and Its Role in Atherosclerosis. Antioxidants. 2019;8(7):218. doi:10.3390/antiox8070218

25.             Rudijanto A. The Expression and Down Stream Effect of Lectin Like-oxidized Low Density Lipoprotein 1 (LOX-1) in Hyperglycemic State. Acta Med Indones. 2007;39(1):8.

26.             Renier G, Maingrette F, Li L. Diabetic Vasculopathy and the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1). Current Diabetes Reviews. 2007;3(2):103-110. doi:10.2174/157339907780598225

27.             Taye A, Saad AH, Kumar AH, Morawietz H. Effect of apocynin on NADPH oxidase-mediated oxidative stress-LOX-1-eNOS pathway in human endothelial cells exposed to high glucose. European Journal of Pharmacology. 2010;627(1):42-48. doi:10.1016/j.ejphar.2009.10.045

28.             Tsai KL, Chen LH, Chiou SH, et al. Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. Molecular Nutrition & Food Research. 2011;55(S2):S227-S240. doi:10.1002/mnfr.201100147

29.             Lubrano V, Balzan S. LOX-1 and ROS, inseparable factors in the process of endothelial damage. Free Radical Research. 2014;48(8):841-848. doi:10.3109/10715762.2014.929122

30.             Quagliariello V, Bonelli A, Paccone A, et al. Oxidized Low-Density Lipoproteins increases nivolumab-induced cardiotoxicity through TLR4/NF-KB and NLRP3 pathways. European Heart Journal. 2021;42(Supplement_1):ehab724.2837. doi:10.1093/eurheartj/ehab724.2837

31.             Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease | European Heart Journal | Oxford Academic. Accessed August 17, 2022. https://academic.oup.com/eurheartj/article/42/18/1797/5960181

32.             Robbesyn F, Salvayre R, Negre-Salvayre A. Dual Role of Oxidized LDL on the NF-KappaB Signaling Pathway. Free Radical Research. 2004;38(6):541-551. doi:10.1080/10715760410001665244

33.             Shu HB, Agranoff AB, Nabel EG, et al. Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-kappa B subunits in endothelial and epithelial cells. Molecular and Cellular Biology. 1993;13(10):6283-6289. doi:10.1128/mcb.13.10.6283-6289.1993

34.             Landry DB, Couper LL, Bryant SR, Lindner V. Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Am J Pathol. 1997;151(4):1085-1095.

35.             Linton MF, Yancey PG, Davies SS, et al. The Role of Lipids and Lipoproteins in Atherosclerosis. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. MDText.com, Inc.; 2000. Accessed August 17, 2022. http://www.ncbi.nlm.nih.gov/books/NBK343489/

36.             Gleissner CA, Leitinger N, Ley K. Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis. Hypertension. 2007;50(2):276-283. doi:10.1161/HYPERTENSIONAHA.107.089854

37.             Berliner JA, Territo MC, Sevanian A, et al. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990;85(4):1260-1266. doi:10.1172/JCI114562

38.             Review. 1996;34(8):599-608. doi:10.1515/cclm.1996.34.8.599

39.             Keidar S, Kaplan M, Aviram M. Angiotensin II–Modified LDL Is Taken Up by Macrophages Via the Scavenger Receptor, Leading to Cellular Cholesterol Accumulation. Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16(1):97-105. doi:10.1161/01.ATV.16.1.97

40.             Gerszten RE, Garcia-Zepeda EA, Lim YC, et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398(6729):718-723. doi:10.1038/19546

41.             Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(11):2292-2301. doi:10.1161/ATVBAHA.107.149179

42.             Moore K, Sheedy F, Fisher E. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13(10):709-721. doi:10.1038/nri3520

43.             Yu XH, Fu YC, Zhang DW, Yin K, Tang CK. Foam cells in atherosclerosis. Clinica Chimica Acta. 2013;424:245-252. doi:10.1016/j.cca.2013.06.006

44.             Shiratsuch H, Basson MD. Differential regulation of monocyte/macrophage cytokine production by pressure. The American Journal of Surgery. 2005;190(5):757-762. doi:10.1016/j.amjsurg.2005.07.016

45.             Fadok V, McDonald P, Bratton D, Henson P. Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochemical Society transactions. 1998;26:653-656. doi:10.1042/bst0260653

46.             Fibrous cap formation or destruction — the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation | Cardiovascular Research | Oxford Academic. Accessed August 17, 2022. https://academic.oup.com/cardiovascres/article/41/2/345/306741

47.             Niu C, Wang X, Zhao M, et al. Macrophage Foam Cell–Derived Extracellular Vesicles Promote Vascular Smooth Muscle Cell Migration and Adhesion. Journal of the American Heart Association. 5(10):e004099. doi:10.1161/JAHA.116.004099

48.             Boyle JJ. Macrophage Activation in Atherosclerosis: Pathogenesis and Pharmacology of Plaque Rupture. Current Vascular Pharmacology. 2005;3(1):63-68. doi:10.2174/1570161052773861

49.             HEREMBERT T, GOGUSEV J, ZHU DL, DRUEKE TB, MARCHE P. Control of vascular smooth-muscle cell growth by macrophage-colony-stimulating factor. Biochemical Journal. 1997;325(1):123-128. doi:10.1042/bj3250123

50.             Fakhry M, Roszkowska M, Briolay A, et al. TNAP stimulates vascular smooth muscle cell trans-differentiation into chondrocytes through calcium deposition and BMP-2 activation: Possible implication in atherosclerotic plaque stability. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2017;1863(3):643-653. doi:10.1016/j.bbadis.2016.12.003

51.             Stary HC. The development of calcium deposits in atherosclerotic lesions and their persistence after lipid regression. The American Journal of Cardiology. 2001;88(2, Supplement 1):16-19. doi:10.1016/S0002-9149(01)01713-1

52.             Pugliese G, Iacobini C, Fantauzzi CB, Menini S. The dark and bright side of atherosclerotic calcification. Atherosclerosis. 2015;238(2):220-230. doi:10.1016/j.atherosclerosis.2014.12.011