Low-density lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL and HDL, that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream. Medically, estimates of cholesterol content carried by LDL particles are used as part of a cholesterol blood test; direct LDL measurements are also available. Since higher levels of LDL particles can promote medical problems like cardiovascular disease, they are often called the bad cholesterol particles, (as opposed to HDL particles, which are frequently referred to as good cholesterol or healthy cholesterol particles).[1] Direct LDL particle measurement by NMR was recognized by the ADA and ACC, in a 03/28/2008 joint consensus statement[2], as superior for predicting risk of atherosclerosis disease events.

Contents

Biochemistry

Structure

Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues), which circulates the fatty acids, keeping them soluble in the aqueous environment. In addition, LDL has a highly-hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and about 1500 esterified cholesterol molecules. This core is surrounded by a shell of phospholipids and unesterified cholesterol, as well as a single copy of B-100 large protein (514 kD). LDL particles are approximately 22 nm (0.00000087 in.) in diameter and have a mass of about 3 million daltons, but since LDL particles contain a changing number of fatty acids, they actually have a distribution of mass and size.[3]

LDL subtype patterns

LDL particles vary in size and density, and studies have shown that a pattern that has more small dense LDL particles, called Pattern B, equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles (Pattern A). This is because the smaller particles are more easily able to penetrate the endothelium. Pattern I, for intermediate, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).

The correspondence between Pattern B and CHD has been suggested by some in the medical community to be stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test has been used more commonly.

There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense LDL.[4][5]

With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy,[6] research studies have continued to show a stronger correlation between human clinically obvious cardiovascular event and quantitatively-measured particle concentrations.

Transport into the cell

When a cell requires cholesterol, it synthesizes the necessary LDL receptors, and inserts them into the plasma membrane. The LDL receptors diffuse freely until they associate with clathrin-coated pits. LDL particles in the blood stream bind to these extracellular LDL receptors. The clathrin-coated pits then form vesicles that are endocytosed into the cell.

After the clathrin coat is shed, the vesicles deliver the LDL and their receptors to early endosomes, onto late endosomes to lysosomes. Here the cholesterol esters in the LDL are hydrolysed. The LDL receptors are recycled back to the plasma membrane.

Medical relevance

Because LDL particles can also transport cholesterol into the artery wall, retained there by arterial proteoglycans and attract macrophages which engulf the LDL particles and start the formation of plaques, increased levels are associated with atherosclerosis. Over time vulnerable plaques rupture, activate blood clotting and produce arterial stenosis, which if severe enough results in heart attack, stroke, and peripheral vascular disease symptoms and major debilitating events.

Increasing evidence has revealed that the concentration and size of the LDL particles more powerfully relates to the degree of atherosclerosis progression than the concentration of cholesterol contained within all the LDL particles.[7] The healthiest pattern, though relatively rare, is to have small numbers of large LDL particles and no small particles. Having small LDL particles, though common, is an unhealthy pattern; high concentrations of small LDL particles (even though potentially carrying the same total cholesterol content as a low concentration of large particles) correlates with much faster growth of atheroma, progression of atherosclerosis and earlier and more severe cardiovascular disease events and death.

LDL particles are formed as VLDL lipoproteins lose triglyceride through the action of lipoprotein lipase (LPL) and they become smaller and denser (i.e. fewer fat molecules with same protein transport shell), containing a higher proportion of cholesterol esters [2].

A hereditary form of high LDL is familial hypercholesterolemia (FH). Increased LDL is termed hyperlipoproteinemia type II (after the dated Fredrickson classification).

LDL particles pose a risk for cardiovascular disease when they invade the endothelium and becomes oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL particles, chiefly stimulated by presence of necrotic cell debries [3] and free radicals in the endothelium.

Role in the innate immune system

LDL lipoproteins interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding Apolipoprotein B, to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.[8]

Lowering LDL

The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component in the pathway.

Pharmaceutical

Statins (HMG-CoA reductase inhibitors) reduce high levels of LDL particles. Statins inhibit the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased, resulting in an increased clearance of LDL particles from the blood.

Ezetimibe reduces intestinal absorption of cholesterol, thus can powerfully augment the LDL particle concentrations when combined with any of the statins.

Niacin (B3), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74[9] and HM74A or GPR109A.[10]

Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.[11]. Other, more recently developed and tested fibrates, e.g. fenofibric acid [4] have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.

Some Tocotrienols, especially d- and ?-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, ?-tocotrienol appears to be another HMG-CoA reductase inhibitor and can reduce cholesterol production.[12] As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how the benefits and complications of such agents will compare with the statins, molecular tools which have been analyzed, since the mid-1970s, in large numbers of human research and clinical trials.

Dietary

The most effective approach has been minimizing visceral (in addition to total) body fat stores. Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of Diabetes Mellitus.

Insulin induces HMG-CoA reductase activity, whereas glucagon downregulates it.[13] While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the digestion of carbohydrates into glucose and subsequent increase in serum glucose levels. In non-diabetics, glucagon levels are very low when insulin levels are high; however, those who have become diabetic no longer suppress glucagon output after eating.

A ketogenic diet may have similar response to taking niacin (lowered LDL and increased HDL) through beta-hydroxybutyrate, a ketone body, coupling the niacin receptor (HM74A).[10]

Lowering the blood lipid concentration of triglycerides helps lower the concentration of LDL particles, because VLDL particles converted in the bloodstream into LDL particles.

Fructose, a component of sucrose as well as high-fructose corn syrup, upregulates hepatic VLDL synthesis.[14]

Importance of antioxidants

Because LDL particles appear to be harmless until within the blood vessel walls and oxidized by free radicals,[15] it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.[16]

Estimation of LDL Cholesterol Values

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. However, there is increasing evidence and recognition of the value of more sophisticated measurements. To be specific, LDL particle number (concentration), and to a lesser extent size, have shown much tighter correlation with atherosclerotic progression and cardiovascular events than is obtained using chemical measures of total LDL concentration contained within the particles. LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Also, LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is tracked against event rates, many other statistical correlates of cardiovascular events, such as diabetes mellitus, obesity, and smoking, lose much of their additional predictive power.

The lipid profile does not measure LDL level directly but instead estimates it using the Friedewald equation[5][17] using levels of other cholesterol such as HDL:

H \approx C - L - kT
where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T are triglycerides, and k is 0.20 if the quantities are measured in mg/dl and 0.45 if in mmol/l.

There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at LDL-C levels 2.5 to 4.5 mmol/L, this formula is considered to be inaccurate.[18] If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities are in mg/dl, may be used

L = C - H - 0.16T

This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer. (However, the concentration of LDL particles, and to a lesser extent their size, has far tighter correlation with clinical outcome than the content of cholesterol with the LDL particles, even if the LDL-C estimation is about correct.)

Normal ranges

In the USA, the American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of 2003, these guidelines were:[19][20][21]

Level mg/dL Level mmol/L Interpretation
<100 <2.6 Optimal LDL cholesterol, corresponding to reduced, but not zero, risk for heart disease
100 to 129 2.6 to 3.3 Near optimal LDL level
130 to 159 3.3 to 4.1 Borderline high LDL level
160 to 199 4.1 to 4.9 High LDL level
>200 >4.9 Very high LDL level, corresponding to highest increased risk of heart disease

These guidelines were based on a goal of presumably decreasing death rates from cardiovascular disease to less than 2% to 3% per year or less than 20% to 30% every 10 years. Note that 100 is not considered optimal; less than 100 is optimal, though it is unspecified how much less.

Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, has been the most effective strategy for reducing cardiovascular death rates in large double blind, randomized clinical trials;[22] far more effective than coronary angioplasty/stenting or bypass surgery.

For instance, for people with known atherosclerosis diseases, the 2004 updated American Heart Association, NIH and NCEP recommendations are for LDL levels to be lowered to less than 70 mg/dL, unspecified how much lower. This low level of less than 70 mg/dL was recommended for primary prevention of 'very-high risk patients' and in secondary prevention as a 'reasonable further reduction'. Lack of evidence for such a recommendation is discussed in an article in the Annals of internal medicine[23]. It should also be noted that statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of LDL levels.

It has been estimated from the results of multiple human pharmacologic LDL lowering trials that LDL should be lowered to about 50 to reduce cardiovascular event rates to near zero. For reference, from longitudinal population studies following progression of atherosclerosis-related behaviors from early childhood into adulthood, it has been discovered that the usual LDL in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not LDLipoprotein concentrations, probably not the better approach.

The feasibility of these figures has been questioned by sceptics, claiming that many members of the AHA and NIH are heavily associated with pharmaceutical companies giving them bias towards lowering cholesterol levels and such guidelines giving rise to increased use of cholesterol lowering medicine such as statins.

Moreover, there are publications [24] regarding the risks of low-LDL cholesterol too.

Direct Measurement of LDL Concentration

Direct LDL particle measurement by NMR was recognized by the ADA and ACC, as published in a 03/28/2008 joint consensus statement [5], as superior for predicting individual risk of atherosclerosis disease events. Since the later 1990s, because of the development of NMR measurements, it has been possible, to clinically measure lipoprotein particles at lower cost [under $100 US (including shipping) versus the previous costs of >$400 to >$5,000] and high accuracy. This was made possible by over two decades of work by Jim Otvos[6], the founder of Liposcience [7], along with many others.

Using NMR, the total LDL particle concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who participated in the MESA trial [8].

Optimal ranges

The LDL particle concentrations are typically categorized by percentiles, <20%, 20-50%, 50th-80th%, 80th-95% and >95% groups of the people participating and being tracked in the MESA[9] trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.

MESA Percentile LDL particles nmol/L Interpretation
0-20% <1,000 Those with lowest rate of cardiovascular disease events & low, Optimal LDL particle concentration
20-50% 1,000-1,299 Those with moderate rate of cardiovascular disease events & moderate LDL particle concentration
50-80% 1,300-1,599 Those with Borderline-High rate of cardiovascular disease events & higher LDL particle concentration
89-95% 1,600 to 2,000 Those with High rate of cardiovascular disease events & High LDL particle concentration
>95% >2,000 Those with Very High rate of cardiovascular disease events & Highest LDL particle concentrations

The lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, total and large HDL particle concentrations, along with estimations of Insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.

See also

Footnotes

  1. ↑ LDL and HDL Cholesterol: What's Bad and What's Good?
  2. ↑ John D. Brunzell, MD, FACP, Michael Davidson, MD, FACC, Curt D. Furberg, MD, PhD, Ronald B. Goldberg, MD, Barbara V. Howard, PhD, James H. Stein, MD, FACC, FACP and Joseph L. Witztum, MD Lipoprotein Management in Patients With Cardiometabolic Risk, J Am Coll Cardiol, 2008; 51:1512-1524. [1]
  3. ↑ Segrest JP, Jones MK, De Loof H, Dashti N (September 2001). "Structure of apolipoprotein B-100 in low density lipoproteins". Journal of Lipid Research 42 (9): 1346–67. PMID 11518754. http://www.jlr.org/cgi/pmidlookup?view=long&pmid=11518754. 
  4. ↑ Superko HR, Nejedly M, Garrett B (2002). "Small LDL and its clinical importance as a new CAD risk factor: a female case study". Progress in Cardiovascular Nursing 17 (4): 167–73. doi:10.1111/j.0889-7204.2002.01453.x. PMID 12417832. 
  5. ↑ 5.0 5.1 Warnick GR, Knopp RH, Fitzpatrick V, Branson L (January 1990). "Estimating low-density lipoprotein cholesterol by the Friedewald equation is adequate for classifying patients on the basis of nationally recommended cutpoints". Clinical Chemistry 36 (1): 15–9. PMID 2297909. http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=2297909. 
  6. ↑ Otvos J (June 1999). "Measurement of triglyceride-rich lipoproteins by nuclear magnetic resonance spectroscopy". Clin Cardiol 22 (6 Suppl): II21–7. PMID 10376193. 
  7. ↑ Not All Calories Are Created Equal, Author Says. Talk of the Nation discussion of the book Good Calories, Bad Calories, by Gary Taubes. National Public Radio, 2 Nov 2007.
  8. ↑ Peterson MM, Mack JL, Hall PR, et al. (December 2008). "Apolipoprotein B Is an innate barrier against invasive Staphylococcus aureus infection". Cell Host & Microbe 4 (6): 555–66. doi:10.1016/j.chom.2008.10.001. PMID 19064256. 
  9. ↑ Meyers CD, Kamanna VS, Kashyap ML (December 2004). "Niacin therapy in atherosclerosis". Current Opinion in Lipidology 15 (6): 659–65. doi:10.1097/00041433-200412000-00006. PMID 15529025. 
  10. ↑ 10.0 10.1 Soudijn W, van Wijngaarden I, Ijzerman AP (May 2007). "Nicotinic acid receptor subtypes and their ligands". Medicinal Research Reviews 27 (3): 417–33. doi:10.1002/med.20102. PMID 17238156. 
  11. ↑ "WHO cooperative trial on primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators". Lancet 2 (8403): 600–4. September 1984. PMID 6147641. 
  12. ↑ Song, B.L.; DeBose-Boyd, R.A. (2006). "Insig-Dependent Ubiquitination and Degradation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Stimulated by Delta- and Gamma-Tocotrienols". J. Biol. Chem. 281 (35): 25054–25601. doi:10.1074/jbc.M605575200. PMID 16831864. 
  13. ↑ Regulation of Cholesterol Synthesis
  14. ↑ Fructose, insulin resistance, and metabolic dyslipidemia
  15. ↑ Inhibition of in vitro human LDL oxidation by phenolic antioxidants from grapes and wines. Teissedre, P.L. : Frankel, E.N. : Waterhouse, A.L. : Peleg, H. : German, J.B. J-sci-food-agric. Sussex : John Wiley : & : Sons Limited. Jan 1996. v. 70 (1) p. 55-61.
  16. ↑ Esterbauer H, Puhl H, Dieber-Rotheneder M, Waeg G, Rabl H (1991). "Effect of antioxidants on oxidative modification of LDL". Annals of Medicine 23 (5): 573–81. doi:10.3109/07853899109150520. PMID 1756027. 
  17. ↑ Friedewald WT, Levy RI, Fredrickson DS (June 1972). "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge". Clinical Chemistry 18 (6): 499–502. PMID 4337382. http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=4337382. 
  18. ↑ Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J (October 2003). "Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula". Clinical Biochemistry 36 (7): 499–504. doi:10.1016/S0009-9120(03)00117-6. PMID 14563441. 
  19. ↑ "Cholesterol Levels". American Heart Association. http://www.americanheart.org/presenter.jhtml?identifier=4500. Retrieved 2009-11-14. 
  20. ↑ "What Do My Cholesterol Levels Mean?" (PDF). American Heart Association. September 2007. http://www.americanheart.org/downloadable/heart/119618151049911%20CholLevels%209_07.pdf. Retrieved 2009-11-14. 
  21. ↑ "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary". National Heart, Lung, and Blood Institute (NHLBI). National Institutes of Health. May 2001. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf. 
  22. ↑ Shepherd J, Cobbe SM, Ford I, et al. (November 1995). "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group". The New England Journal of Medicine 333 (20): 1301–7. doi:10.1056/NEJM199511163332001. PMID 7566020. 
  23. ↑ Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem
  24. ↑ Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy.

References & External Links

Lipids: lipoprotein metabolism
Apolipoproteins
APOA (1, 2, 4, 5) · APOB · APOC (1, 2, 3, 4) · APOD · APOE · APOH
Lipoproteins
Chylomicron · HDL · LDL · IDL · VLDL · Lp(a)
HDL
Cholesterylester transfer protein · Acetyl-CoA C-acyltransferase · LCAT · ABCA1
LDL
LDL receptor · Microsomal triglyceride transfer protein · APOB
Other
Lipoprotein lipase · SAA

: MET

mt, r//c/p/i/y, f/s/l/o, a/u, n, h

rgcp//y, f/s/l/o, au, n, h,

m(A16, C10),i(//c//i/y, /s/o, a/u,n, h)