Low-density lipoprotein Totally Explained

Everything about Low-density Lipoprotein totally explained

Low-density lipoprotein (LDL) is a lipoprotein that transports cholesterol and triglycerides from the liver to peripheral tissues. LDL also regulates cholesterol synthesis at these sites. It commonly appears in the medical setting as part of a cholesterol blood test, and since high levels of LDL cholesterol can signal medical problems like cardiovascular disease, it's sometimes called "bad cholesterol" (as opposed to HDL, the "good cholesterol").

Biochemistry

Structure

Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that 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 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 mass and size distribution. .

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 and less dense 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.
   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. 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 unfolding of carbohydrates into glucose during the process of digestion. Glucagon levels are very low when insulin levels are high.
   Lowering the blood lipid concentration of triglycerides helps lower the amount of LDL, because VLDL gets converted in the bloodstream into LDL. Fructose, a component of sucrose as well as high-fructose corn syrup, upregulates hepatic VLDL synthesis . Niacin (B₃), which blocks breakdown of fats, also lowers VLDL and, as a consequence, LDL. It comes with the added benefit of increasing high-density lipoprotein, HDL, the so-called 'good' cholesterol.

Importance of antioxidants

Because LDL appears to be harmless until oxidized by free radicals, it's postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.

Measurement of LDL

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they've the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. However, there's 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 doesn't measure LDL level directly but instead estimates it via the Friedewald equation
using levels of other cholesterol such as HDL: ť

extit

In mg/dl: LDL cholesterol = total cholesterol – HDL cholesterol – (0.20 × triglycerides) ť In mmol/l: LDL cholesterol = total cholesterol – HDL cholesterol – (0.45 × triglycerides)

There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C can't be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at LDC-L levels 2.5 to 4.5 mmol/L, this formula is considered to be inaccurate. If both total cholesterol and triglyceride levels are elevated then a modified formula may be used ť In mg/dl: LDL-C = Total-C – HDL-C – (0.16 × Trig)

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:

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% per year or less than 20% to 30% every 10 years. Note that 100 isn't considered optimal; less than 100 is optimal, though it's 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/cholesterol concentration within LDL, not LDLipoprotein concentrations, probably not the better approach.

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