LDL Bad Cholesterol/Low-density lipoprotein (LDL) plays a key role in the development and progression of atherosclerosis and cardiovascular disease. LDL consists of several subclasses of particles with different sizes and densities, including large buoyant (lb) and intermediate and small dense (sd) LDLs. It has been well documented that sdLDL has a greater atherogenic potential than that of other LDL subfractions and that LDL cholesterol (sdLDL-C) proportion is a better marker for the prediction of cardiovascular disease than that of total LDL-C. Circulating sdLDL readily undergoes multiple atherogenic modifications in blood plasma, such as desialylation, glycation, and oxidation, that further increase its atherogenicity.
LDL cholesterol or low-density lipoprotein cholesterol is a fat that circulates in the blood, moving cholesterol around the body to where it is needed for cell repair and depositing it inside of artery walls. Because cholesterol and triglycerides are insoluble in water, they must be associated with proteins to flow through the hydrophilic blood. [rx]
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein which transport all fat molecules around the body in the extracellular water.[rx] These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density naming convention), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.
Issues of Concern
LDL receptor function is needed for the uptake of LDL from the blood into hepatocytes.
Defects in LDL receptor function can cause hypercholesterolemia, known as familial hypercholesterolemia, an autosomal dominant disorder. Because LDL receptors on the surface of hepatocytes are necessary for the binding and subsequent uptake of LDL molecules in the blood, a genetic decrease in LDL receptor number would cause a decreased ability of hepatocytes to absorb LDL and would increase LDL in the blood. If this mutation is heterozygous, some LDL receptors will be present on the hepatocytes thus LDL is usually around 300 mg/dL. However, a homozygous mutation will result in the complete absence of LDL receptors on hepatocytes, increasing the LDL cholesterol levels up to 1000 mg/dL. [rx]
The liver produces Very low-density lipoprotein (VLDL), which is metabolized to IDL by lipoprotein lipase (LPL). IDL is then converted to LDL by hepatic triglyceride lipase (HTGL). LDL and a portion of IDL particles are cleared from the circulation via the LDL receptors (LDL-Rc) expressed in the liver and other cells. [rx]
The LDL receptor consists of a single chain glycoprotein and is 839 amino acids long. It is comprised of a 320 residue N-terminal ectoplasmic domain that contains the LDL-binding site and consists of disulfide-bonded cysteine residues, a C-terminal cytosolic domain which traps the LDL receptor in clathrin-coated pits, and a sequence of 22 hydrophobic amino acids within the plasma membrane in the form of an alpha helix. [rx]
LDL particles bind to an LDL receptor on the plasma membrane, forming a receptor-ligand complex that is internalized in a clathrin-coated pit that pinches off to become a coated vesicle. After endocytosis, the LDL particle and its receptors are internalized by receptor-mediated endocytosis and degraded in the lysozyme. The clathrin coat depolymerizes, forming an early endosome which fuses with a late endosome where the low pH causes the LDL particles to dissociate from the LDL receptors. In the lysozyme, the apo-B protein of the LDL is degraded to amino acids, and cholesterol esters are hydrolyzed to fatty acids and cholesterol. [rx]
Normal Ranges
In the US, 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 about 2005, these guidelines were:[rx][rx][rx]
| Level mg/dL | Level mmol/L | Interpretation |
|---|---|---|
| 25 to <50 | <1.3 | Optimal LDL cholesterol, levels in healthy young children before onset of atherosclerotic plaque in heart artery walls |
| <70 | <1.8 | Optimal LDL cholesterol, corresponding to lower rates of progression, promoted as a target option for those known to clearly have advanced symptomatic cardiovascular disease |
| <100 | <2.6 | Optimal LDL cholesterol, corresponding to lower, but not zero, rates for symptomatic cardiovascular disease events |
| 100 to 129 | 2.6 to 3.3 | Near-optimal LDL level, corresponding to higher rates for developing symptomatic cardiovascular disease events |
| 130 to 159 | 3.3 to 4.1 | Borderline high LDL level, corresponding to even higher rates for developing symptomatic cardiovascular disease events |
| 160 to 199 | 4.1 to 4.9 | High LDL level, corresponding to much higher rates for developing symptomatic cardiovascular disease events |
| >200 | >4.9 | Very high LDL level, corresponding to the highest increased rates of symptomatic cardiovascular disease events |
Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large double-blind, randomized clinical trial of men with hypercholesterolemia;[rx] far more effective than coronary angioplasty/stenting or bypass surgery.[rx]
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 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 the lowest rate of cardiovascular disease events & low (optimal) LDL particle concentration |
| 20–50% | 1,000–1,299 | Those with a 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% | 1,600–2,000 | Those with a high rate of cardiovascular disease events and even higher LDL particle concentration |
| >95% | >2,000 | Those with a very high rate of cardiovascular disease events and highest LDL particle concentration |
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, large total and 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.
What does the test result mean?
In general, healthy lipid levels help to maintain a healthy heart and lower the risk of heart attack or stroke. Your healthcare practitioner will take into consideration the results of the LDL-C and the other components of a lipid panel as well as other risk factors to help determine your overall risk of heart disease, whether treatment is necessary and, if so, which treatment will best help to lower your risk.
Adults
Health organizations have different recommendations for treatment based on your predicted cardiovascular disease (CVD) risk.
Current guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) recommend that a risk calculator be used to determine your 10-year risk of CVD if you are age 40 to 75 and do not have heart disease. Many factors are considered in the calculation, including total cholesterol, LDL-C, HDL-C, age, gender, race, blood pressure, diabetes, and smoking.
ACC and AHA recommend treatment with statins if you:
- Have heart disease (diagnosed by medical history, imaging, etc.)
- Have LDL-C greater than 190 mg/dL (4.90 mmol/L)
- Are age 40 to 75 years with diabetes and LDL-C 70-189 mg/dL (1.81-4.90 mmol/L)
- Are age 40 to 75 years old with LDL-C level between 70-189 mg/dL (1.81-4.90 mmol/L) and 10-year risk of developing heart disease of greater than 7%
The U.S. Preventive Services Task Force (USPSTF) makes recommendations on the use of statins for treatment in adults ages 40 to 75 with no history of heart disease, based on risk factors (i.e., LDL-C greater than 130 mg/dL [3.37 mmol/L], HDL-C less than 40 mg/dL [1.0 mmol/L], diabetes, blood pressure, smoking) and the use of the risk calculator.
- If you have one or more risk factors and a calculated 10-year CVD event risk of 10% or greater, USPSTF recommends the use of a low-to-moderate dose statin.
- If you have one or more risk factors and your calculated 10-year CVD event risk is 7.5% to 10%, USPSTF says your healthcare practitioner may choose to offer a low-to-moderate dose statin. This is because the probability that you will have a CVD event is lower, so the benefit of statin is likely to be smaller.
According to the USPSTF, there is not currently enough evidence to evaluate the utility of screening adults ages 21 to 39 for unhealthy lipid levels, or to assess the benefits and risks of statin use in adults 76 years or older with no history of CVD.
Use of the risk calculator and ACC/AHA guidelines remains controversial and is evolving as more data become available. Some say that the current risk calculator can overestimate risk. Many still use the older guidelines (2002) from the NCEP Adult Treatment Panel (ATP) III to evaluate LDL-C levels and heart disease risk, as summarized below.
| Optimal | Near/Above Optimal | Borderline High | High | Very High |
| Less than 100 mg/dL (2.59 mmol/L); with CVD or diabetes: less than 70 mg/dL (1.81 mmol/L) | 100-129 mg/dL (2.59-3.34 mmol/L) | 130-159 mg/dL (3.37-4.12 mmol/L) | 160-189 mg/dL (4.15-4.90 mmol/L) | Greater than 190 mg/dL (4.90 mmol/L) |
According to NCEP ATP III guidelines, if you have LDL-C above the following target values and risk factors (e.g., family history, cigarette smoking, diabetes, high blood pressure), you require treatment.
The target LDL-C values are
- Less than 100 mg/dL (2.59 mmol/L) if you have heart disease or diabetes [and ideally less than 70 mg/dL [1.81 mmol/L)]
- Less than 130 mg/dL (3.37 mmol/L) if you have 2 or more risk factors
- Less than 160 mg/dL (4.14 mmol/L) if you have 0 or 1 risk factor
Youth
According to the American Academy of Pediatrics, the LDL-C level can be evaluated for youth with no other risk factors as follows:
| Acceptable | Borderline | High | |
| Children and Teens (ages 2 to 18) | Less than 110 mg/dL (2.85 mmol/L) | 110-129 mg/dL (2.85-3.34 mmol/L) | Greater than or equal to 130 mg/dL (3.36 mmol/L) |
| Young Adults (ages 19 to 24) | Less than 120 mg/dL (3.10 mmol/L) | 120-159 mg/dL 3.10-4.11 mmol/L) | Greater than or equal to 160 mg/dL (4.12 mmol/L) |
Low levels of LDL cholesterol are not generally a concern and are not monitored. They may be seen in people with an inherited lipoprotein deficiency and in people with hyperthyroidism, infection, inflammation, or cirrhosis.
The Function of Low-Density Lipoprotein
Apolipoproteins serve a structural role in phospholipid membranes, acting as ligands for lipoprotein receptors, guiding the formation of lipoproteins, and serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins. Lipoproteins are critical for absorption and transport of dietary lipids by the small intestine and moving lipids from the liver to peripheral tissues and back from peripheral tissues to the liver and intestine. They are also crucial for the transport of toxic foreign hydrophobic and amphipathic compounds, including bacterial endotoxin from areas of invasion and infection. [rx]
Mechanism
The LDL receptor is on the liver and most other tissues. It recognizes Apo B 100 and Apo E, mediating the uptake of LDL, chylomicron remnants, and IDL, through endocytosis. After internalization, the lipoprotein particle is degraded in lysosomes, and cholesterol is released. When cholesterol enters the cell, HMG CoA reductase activity increases then synthesizes cholesterol and modulates the expression of LDL receptors. LDL receptors on the liver determine plasma LDL levels. When there is a low number of receptors, less LDL can be taken up from the blood by the liver, leading to high plasma LDL levels. Conversely, when there are more LDL receptors, more LDL is taken up from the blood by the liver, leading to low plasma LDL levels.
Levels of cholesterol regulate the number of LDL receptors in the cell. If the cell senses a decrease in cholesterol levels, the transcription factor SREBP is transported from the endoplasmic reticulum to Golgi where proteases cleave and activate SREBP which moves to the nucleus and increases expression of LDL receptors. When cholesterol levels are low in the cell, high SREBP remains in the endoplasmic reticulum in an inactive form, and the expression of LDL receptors is decreased. [rx]
Treatment or Lowering LDL-cholesterol
| Markers indicating a need for LDL-C Reduction(Per 2004 United States Government Minimum Guidelines[rx][rx]) | ||||
|---|---|---|---|---|
| If the patient’s cardiac risk is… | then the patient should consider LDL-C reduction if the count in mg/dL is over… | and LDL-C reduction is indicated if the count in mg/dL is over… | ||
| High – meaning a 20% or greater risk of heart attack within 10 years, or an extreme risk factor | 70[rx] | 100[rx] | ||
| Moderately high – meaning a 10-20% risk of heart attack within 10 years and more than 2 heart attack risk factors | 100[rx] | 130[rx] | ||
| Moderate – meaning a 10% risk of heart attack within 10 years and more than 2 heart attack risk factors | 130[rx] | 160[rx] | ||
| Low – meaning less than 10% risk of heart attack within 10 years and 1 or 0 heart attack risk factors | 160[rx] | 190[rx] | ||
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 and performs the first of 37 steps within the cholesterol production pathway, and present in every animal cell.
Pharmaceutical
- PCSK9 inhibitors – in clinical trials, by several companies, are more effective for LDL reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe).
- Statins reduce high levels of LDL – particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, the synthesis of LDL receptors (including hepatic) is increased, resulting in an increased clearance of LDL particles from the extracellular water, including of the blood.
- Ezetimibe – reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins.[rx]
- Niacin (B3) – lowers LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74[rx] and HM74A or GPR109A.[rx]
- Several CETP inhibitors – have been researched to improve HDL concentrations, but so far, despite dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates compared with placebo.
- Clofibrate – is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.[rx] Other, more recently developed and tested fibrates, e.g. fenofibric acid[rx] 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 delta- and gamma-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, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor and can reduce cholesterol production.[rx] 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 compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.
- Phytosterols – are widely recognized as having a proven LDL cholesterol-lowering efficacy,[rx] although no scientifically proven beneficial effect on cardiovascular disease (CVD) or overall mortality exists.[rx] Current supplemental guidelines for reducing LDL recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III, FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.[rx]
Lifestyle
- The most effective approach – has been minimizing fat stores located inside the abdominal cavity (visceral body fat) in addition to minimizing total body fat. 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.
- A healthy diet – Try not to eat things that are high in saturated fat, cholesterol, or simple carbs such as sugar and white flour. Eat more fiber and plant sterols such as margarine or nuts.
- Regular exercise – The kind that gets your heart pumping is best.
- Weight loss – Losing even 5 to 10 pounds can improve your cholesterol levels.
- Quitting tobacco – If you have a hard time giving up smoking, your doctor can help you find the program that’s best for you.
References
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