Low density lipoprotein

Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying in their size (18-25 nm in diameter) and contents, which carry fatty acid molecules in the blood and around the body, for use by cells. It is the final stage of VLDL (very low-density lipoprotein) which is produced by the liver. The LDL contains the apolipoproteins B-100 (Apo B-100, a protein with 4536 amino acid residues) and Apo E.|volume=341|pages=162-164}} It also contains antioxidative vitamins (vitamin E or carotinoids). It is commonly referred to as "bad cholesterol" due to the link between high LDL levels and cardiovascular disease.

Function

Generally, LDL transports cholesterol and triglycerides away from cells and tissues that produce more than they use, towards cells and tissues which are taking up cholesterol and triglycerides.

Role in disease

Because LDL transports cholesterol to the arteries, increased levels are associated with atherosclerosis, and thus myocardial infarctions, strokes and peripheral vascular disease. This is why cholesterol inside LDL lipoproteins is called bad cholesterol. Still, it is not the cholesterol that is bad; it is instead how and where it is being transported, and in what amounts over time.

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. The healthiest pattern, though realtively 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 is formed as VLDL lipoproteins, which lose triglyceride through the action of lipoprotein lipase (LPL), and become smaller and denser containing a higher proportion of cholesterol.

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

LDL poses a risk for cardiovascular disease when it invades the endothelium and becomes oxidized. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of free radicals in the endothelium. Nitric oxide down-regulates this oxidation process catalyzed by L-arginine. Correspondingly when there are high levels of asymmetric dimethylarginine in the endothelium, production of nitric oxide is inhibited and more LDL oxidation occurs.

Recommended range; changing targets

The American Heart Association, NIH and NCEP provide a set of guidelines for fasting LDL levels and risk for heart disease. As of 2003, these guidelines were:

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 189	4.1 to 4.9	High LDL level
>190	>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%/year or less than 20 to 30%/10 years. Also notice that 100 is not considered optimal, but less than 100, 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; 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. 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 concentration, probably not the better approach.

Measurement methods

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. Specifically, 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. Alternatively, 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 additive predictive power.

LDL subtype patterns

LDL particles actually 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, "fluffy" LDL particles ("Pattern A"). This is because the smaller particles are more easily able to penetrate the endothelium. "Pattern I", meaning "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.

The lipid profile does not measure LDL level directly but instead estimates it via the Freidwald equation using levels of other cholesterol such as HDL:

\textit{LDL-C} \approx \textit{Total\ cholesterol} - \textit{HDL-C} - 0.20 * \textit{Total\ triglycerides}

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.)

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, fluffier LDL. [http://www.clinchem.org/cgi/content/abstract/36/1/15.

With the decreasing cost, greater availability, wider acceptance and research use of other lipoprotein assay methods, especially NMR spectroscopy, ongoing research studies have shown the strongest correlation between human clinically obvious cardiovascular event rates has been with quantitatively measured particle concentrations, more so than particle size and particle cholesterol/lipid content.

Function

Role in disease

Recommended range; changing targets

Measurement methods

LDL subtype patterns

Citations

References

See also

Gourt Home::Gourt :: Low density lipoprotein

Function

Role in disease

Recommended range; changing targets

Measurement methods

LDL subtype patterns

Citations

References

See also