HDL cholesterol

HDL stands for high density lipoprotein or HDL-C (high-density lipoprotein cholesterol). HDL is sometimes called “good cholesterol” because it carries harmful cholesterol from other parts of your body including your arteries back to your liver. Your liver then removes the cholesterol from your body and helps protect you from heart attack and stroke. A healthy HDL-cholesterol level may protect against heart attack and stroke ¹, ², ³. If you have low HDL levels, you have a greater heart disease risk, even if your total cholesterol is below 200 mg/dL ⁴, ⁵. However, several recent investigations, including many clinical trials focusing on increasing HDL cholesterol levels with drug therapies did not show any beneficial effect on cardiovascular disease ⁶, ⁷, starting a lively debate about the appropriateness of HDL as a therapeutic target. A recent meta-analysis reported that the total number of HDL particles, as well as numbers of small and medium, but less so large HDL particles, are associated with incident of atherosclerotic cardiovascular diseases ⁸, ⁹. A recent Mendelian randomization study found genetically causal associations of coronary artery disease or heart attack (myocardial infarction) with the concentrations of medium and small HDL particles, but not with large HDL particles ¹⁰, ¹¹. This heterogeneity is potentially important since lipid-modifying drugs cause diverse changes in HDL particle size, number, and composition. Treatment with nicotinic acid and CETP inhibitors increases HDL cholesterol levels more profoundly than HDL particles, while treatment with fibrates increases HDL particles more strongly than HDL cholesterol ¹². Recent large epidemiological studies showed extremely high levels of HDL cholesterol had an adverse effect on death from atherosclerotic cardiovascular disease ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷. In addition, HDL is a rather complex family of different particles, being composed of sub-species differing in size, density, shape, charge, and composition, undergoing continuous remodelling processes in your blood ¹⁸. This remarkable heterogeneity of the HDL particle family may explain why HDL cannot always be considered ‘anti-atherogenic’, but can sometimes become dysfunctional or even ‘pro-atherogenic’ ¹⁹. This new insight into the complex functions of HDL has reinforced the idea that HDL is not merely a cholesterol transporter, but, rather possesses several additional functional properties including cholesterol efflux capacity, anti-oxidant, anti-inflammatory, and immune-regulating activities ¹⁸. This led to the suggestion that the functionality of HDL, that is determined by its composition and post-translational modifications are more important determinants for protection against cardiovascular disease than the HDL cholesterol levels of  ²⁰, ²¹.

Cholesterol travels through your blood on proteins called lipoproteins (see Figure 2). High density lipoprotein (HDL) is the smallest circulating lipoprotein and is found near all cells. HDLs are predominantly spherical particles of varying size, surface charge and lipid and apolipoprotein composition ²². All HDLs have the same overall structure: a water insoluble, neutral lipid core mainly cholesteryl esters and some triglycerides surrounded by a surface monolayer mainly phospholipids and some unesterified cholesterol in which apolipoproteins are embedded (see Figure 1) ¹⁹. Particles with a hydrophobic neutral lipid core form spherical-like structures approximately 8–11 nm in diameter (referred to as α-migrating HDL, based on their migration on agarose gel), whereas particles depleted of neutral lipids form disc-like structures ²². Detailed analysis of HDL particle revealed the existence of two major HDL apolipoproteins, apolipoprotein A-I (apoA-1 or APOA1) and apolipoprotein A-2 (apoA-II) that account for ~70% and ~20% of HDL protein mass, with small amounts of other apoproteins such as apoA-IV, apoA-V, apoC and apoE ²³, ²⁴, ²⁵, ²⁶, ²⁷. Additionally, HDL has been shown to contain a lot more proteins (>80) like the lipocalins apoD and apoM ²⁸. Due to differences in apolipoproteins (Apo), phospholipids, cholesterol and cholesteryl esters, high density lipoproteins have differences in surface charge and density and can thereby be classified into Gamma (γ-), Alpha (α-) or preBeta (preβ-) migrating particles or into larger-sized, lower-density (HDL2a and HDL2b) and smaller-sized, higher-density (HDL3a, HDL3b, and HDL3c) sub-classes ²⁹, ³⁰, ³¹.

Historically, HDL was first sub-fractionated based on the density of lighter and larger HDL2 (HDL2a and HDL2b) and heavier and smaller HDL3 (HDL3a, HDL3b, and HDL3c) sub-fractions ³². Another early classification of HDL sub-fractions was based on the presence or absence of apoA-II, the second most abundant protein in HDL. These types of classifications had, however, limited impact on routine diagnostic testing, because of lacking evidence for superiority ¹⁹. Separation of HDL into discrete HDL size fractions can now be readily done by nuclear magnetic resonance (NMR) spectroscopy in clinical laboratories, providing the ratio of large-to-small HDL, which may be useful for assessing not only cardiovascular risk but also insulin resistance and other conditions ³². Recent advances in mass spectrometry allow the comprehensive quantification of the proteome in total HDL as well as distinct sub-classes ³³, ³⁴, ³⁵, ³⁶. At this time, there is only limited commercial availability of these advanced HDL sub-fractionation tests and hence they are not widely used but they are being actively investigated for their clinical utility ¹⁹.

From a functional point of view, HDL cholesterol is not a causal marker because the many functions of HDL are exerted either by entire HDL particles or specific components other than cholesterol ¹⁹. Furthermore, low HDL cholesterol is strongly associated with increased levels of triglyceride-rich lipoproteins. Low HDL levels are nowadays widely considered as an indirect and non-causal biomarker of elevated atherosclerotic cardiovascular disease risk reflecting the atherogenicity of elevated plasma levels of triglyceride-rich lipoprotein and their remnants ³⁷. Both low and extremely high HDL levels are associated with an increased risk of all-cause mortality ¹⁴.

Your doctor will evaluate your HDL and other cholesterol levels and other factors to assess your risk for heart attack or stroke. People with high blood triglycerides usually also have lower levels of HDL. Genetic factors, type 2 diabetes, smoking, being overweight and being sedentary can all lower HDL cholesterol. Women tend to have higher levels of HDL cholesterol than men do, because the female hormone estrogen raises HDL, but this can change after menopause.

Experts believe HDL cholesterol may act in a variety of helpful ways that tend to reduce the risk for heart disease ³⁸:

• HDL cholesterol scavenges and removes LDL or “bad” cholesterol.
• HDL reduces, reuses, and recycles LDL cholesterol by transporting it to the liver where it can be reprocessed.
• HDL cholesterol acts as a maintenance crew for the inner walls (endothelium) of blood vessels. Damage to the inner walls is the first step in the process of atherosclerosis, which causes heart attacks and strokes. HDL scrubs the wall clean and keeps it healthy.
• HDL cholesterol below 40mg/dL are strongly associated with increased risk of coronary artery disease and peripheral arterial disease and are characterized by an atherogenic dyslipidemia consisting of high levels of LDL particles, elevated triglycerides and increased insulin resistance.
• Low HDL cholesterol levels are associated with an increased risk of autoimmune disease ³⁹ and cancer ⁴⁰, ⁴¹, ⁴², ⁴³; for cancer, the risk increase was more pronounced for low apoA-I than for low HDL leve ⁴¹, suggesting that HDL particles rather than their cholesterol content drive this association.
• High HDL cholesterol 60 mg/dL or higher is Protective against heart disease.
• Several recent investigations, including many clinical trials focusing on increasing HDL cholesterol levels with drug therapies did not show any beneficial effect on cardiovascular disease ⁶, ⁷. A recent meta-analysis reported that the total number of HDL particles, as well as numbers of small and medium, but less so large HDL particles, are causal associations of coronary artery disease or atherosclerotic cardiovascular disease ⁸, ¹⁰, ⁹. A recent Mendelian randomization study found genetically causal associations of coronary artery disease or heart attack (myocardial infarction) with the concentrations of medium and small HDL particles, but not with large HDL particles ¹⁰, ¹¹.
• Recent large epidemiological studies showed extremely high levels of HDL cholesterol had an adverse effect on death from atherosclerotic cardiovascular disease ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷. In addition, HDL is a rather complex family of different particles, being composed of sub-species differing in size, density, shape, charge, and composition, undergoing continuous remodelling processes in your blood ¹⁸. This remarkable heterogeneity of the HDL particle family may explain why HDL cannot always be considered ‘anti-atherogenic’, but can sometimes become dysfunctional or even ‘pro-atherogenic’ ¹⁹. This new insight into the complex functions of HDL has reinforced the idea that HDL is not merely a cholesterol transporter, but, rather possesses several additional functional properties including cholesterol efflux capacity, anti-oxidant, anti-inflammatory, and immune-regulating activities ¹⁸. This led to the suggestion that the functionality of HDL, that is determined by its composition and post-translational modifications are more important determinants for protection against cardiovascular disease than the HDL cholesterol levels of  ²⁰, ²¹.
• Despite the clinical utility of low HDL cholesterol, the associations between HDL cholesterol and atherosclerotic cardiovascular disease are not linear and vary according to race or ethnicity. There is a U-shaped association between HDL cholesterol and atherosclerotic cardiovascular disease mortality, with a linear inverse association preserved below 40mg/dL HDL in men and below 50-58 mg/dL HDL in women, no association across the normal range (40-96 mg/dL in men and 50-134 mg/dL in women), and a modest but increased atherosclerotic cardiovascular disease risk at HDL cholesterol levels above 90 mg/dL in Asians, above 97 mg/dL in White male and above 135 mg/dL in White female populations ⁴⁰, ¹⁷. Moreover, the links between HDL cholesterol and atherosclerotic cardiovascular disease among Blacks may be attenuated or even trend in the opposite direction compared to Whites ⁹.

People with high blood triglycerides usually also have lower HDL cholesterol. Genetic factors, type 2 diabetes, smoking, being overweight and being sedentary can all lower HDL cholesterol. Women tend to have higher levels of HDL cholesterol than men do.

A healthy HDL cholesterol level may protect against heart attack and stroke. Studies show low levels of HDL cholesterol increase the risk of heart disease. HDL cholesterol does not completely eliminate LDL cholesterol. Only one-fourth to one-third of blood cholesterol is carried by HDL.

HDL levels should be around 50 mg/dL. Some people can raise HDL by::

• Exercising for at least 30 minutes 5 times a week
• Quitting smoking
• Avoiding saturated fats
• Losing weight

Others may need medicine to get HDL to a beneficial level, and should work with your doctor on a treatment plan.

Figure 1. HDL cholesterol structure

Footnotes: Generalized structure of high-density lipoprotein (HDL) cholesterol. High-density lipoprotein (HDL) particles carry a large number of proteins and lipids, which contribute to their compositional and functional complexity. High-density-lipoproteins (HDL) particles consist of a core of triglycerides and cholesteryl esters. This core is surrounded by a phospholipid monolayer containing unesterified cholesterol and several apoproteins (mostly apoA-1). In their mature form, HDL contains a nonpolar lipid core mainly consisting of cholesteryl esters and triglycerides surrounded by a single surface monolayer of phospholipids (mainly phosphatidylcholine), unesterified cholesterol and amphipathic apolipoproteins. Based the presence of absence of cholesteryl esters, HDL has either a discoidal or a spherical shape. HDL can be further subdivided into larger-sized, lower-density (HDL2a and HDL2b) and smaller-sized, higher-density (HDL3a, HDL3b, and HDL3c) sub-classes ²⁹. Apolipoproteins associated with HDL can undergo post-translational modifications. The major apolipoprotein constituents of HDL are apoA-I (70%) and apoA-II (20%), with small amounts of other apoproteins such as apoA-IV, apoA-V, apoC and apoE ²⁷. Additionally, HDL has been shown to contain a lot more proteins (>80) like the lipocalins apoD and apoM ²⁸.

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Figure 2. Lipoprotein

Footnotes: General overview of HDL metabolism. Apolipoprotein A-I (ApoA-I) is produced in the liver and intestines and subsequently forms discoidal HDL after interacting with the ATP-binding cassette transporter A1 (ABCA1). Continued cholesterol export via ABCG1 and via scavenger receptor class B member 1 (SR-B1) in macrophages and enzymatic reactions mediated by lecithin-cholesterol acyltransferase (LCAT) result in the conversion into spherical HDL3 and HDL2 particles. Cholesterol and cholesteryl esters can be transferred to the liver by two main pathways, directly through binding to scavenger receptor class B member 1 (SR-B1) in the liver and subsequent excretion via the kidneys, or indirectly by being transferred to very-low-density lipoproteins (VLDL), intermediate-density-lipoproteins (IDL) and low-density lipoproteins (LDL) by cholesteryl ester transfer protein (CETP), followed by uptake of these lipoproteins via the LDL receptor (LDLR) in liver cells (hepatocytes). Additionally, HDL can be catabolized in the liver via its uptake as holoparticles through a yet to be identified HDL receptor (HDLR). HDL2 can be remodeled by processes that are catalyzed by hepatic lipase (HL), endothelial lipase (EL) and plasma phospholipid transfer protein (PLTP), resulting in the formation of lipid-poor HDL particles which again interact with ATP-binding cassette transporter A1 (ABCA1) for a next lipidation cycle.

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Figure 4. Cholesterol transfers between high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and cells.

Abbreviations: ABCA1 = ATP-binding cassette transporter A1; ABCG1 = ATP-binding cassette transporter G1; CE = cholesteryl ester; CETP = cholesteryl ester transfer protein; FC = free cholesterol, unesterified cholesterol; HDL = high-density lipoprotein; HL = hepatic lipase; LCAT = lecithin:cholesterol acyltransferase; LDL = low-density lipoprotein; LPL = lipoprotein lipase; PLTP = phospholipid transfer protein; SR-B1 = scavenger receptor B1.

[Source ¹⁹ ]

Figure 5. High-density lipoprotein levels and risk of all-cause mortality in men and women

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What is cholesterol?

Cholesterol is a waxy, fat-like substance that’s found in all the cells in your body. Cholesterol is produced by your liver, adrenal glands, intestines, and in gonads and 20 to 25% of cholesterol comes from your diet (foods you eat) ⁴⁵. Cholesterol is an essential component of all cell membranes – it helps to maintain structural integrity and fluidity of cell membranes, allowing your cells to change shapes easily without cell walls ⁴⁶. More than 90% of cellular cholesterol is located at the plasma membrane ⁴⁷. Your body needs some cholesterol to make hormones such as testosterone and estrogen, vitamin D and the biosynthesis of bile acids in your liver that help you digest foods ⁴⁸, ⁴⁹, ⁵⁰.

Cholesterol travels through your blood on proteins called lipoproteins. One type, LDL (low-density lipoprotein), is sometimes called the “bad” cholesterol. A high LDL level leads to a buildup of cholesterol in your arteries. Another type, HDL (high-density lipoprotein), is sometimes called the “good” cholesterol. HDL carries cholesterol from other parts of your body back to your liver. Then your liver removes the cholesterol from your body.

Types of cholesterol:

• HDL stands for high-density lipoprotein or HDL-C (high-density lipoprotein cholesterol). HDL is sometimes called “good cholesterol” because it carries harmful cholesterol from other parts of your body including your arteries back to your liver. Your liver then removes the cholesterol from your body and helps protect you from heart attack and stroke. A healthy HDL-cholesterol level may protect against heart attack and stroke. If you have low HDL levels, you have a greater heart disease risk, even if your total cholesterol is below 200 mg/dL. Your doctor will evaluate your HDL and other cholesterol levels and other factors to assess your risk for heart attack or stroke. People with high blood triglycerides usually also have lower levels of HDL. Genetic factors, Type 2 diabetes, smoking, being overweight and being sedentary can all lower HDL cholesterol. Women tend to have higher levels of HDL cholesterol than men do, because the female hormone estrogen raises HDL, but this can change after menopause.
• LDL stands for low-density lipoprotein or LDL-C (low-density lipoprotein cholesterol). LDL is sometimes called “bad cholesterol” because a high LDL level leads to the buildup of plaque in your arteries. LDL is the most important lipid for predicting your heart disease risk. Low-density lipoprotein (LDL or ‘bad’) cholesterol can join with fats and other substances to build up (also known as plaque) in the inner walls of your arteries, which starts a disease process called atherosclerosis. The arteries can become clogged and narrow, and blood flow is reduced. When plaque builds up in your coronary arteries that supply blood to your heart, you are at greater risk of having a heart attack. Since LDL is the bad kind of cholesterol, a low LDL level is considered good for your heart health. A diet high in saturated and trans fat is unhealthy because it tends to raise LDL cholesterol levels. Your LDL levels may be high if you eat a diet with a lot of saturated fat, cholesterol, or both. Sometimes, an under-active thyroid called hypothyroidism may also increase LDL levels.
• VLDL stands for very low-density lipoprotein or VLDL-C (very low-density lipoprotein cholesterol). Some people also call VLDL a “bad cholesterol” because it too contributes to the buildup of plaque in your arteries. But VLDL and LDL are different; VLDL mainly carries triglycerides and LDL mainly carries cholesterol. VLDL particles are released into the blood by the liver and circulate in the bloodstream, ultimately being converted into LDL as they lose triglyceride, having carried it to other parts of the body. According to the National Heart, Lung and Blood Institute’s National Cholesterol Education Program Guidelines ATP III, there is growing evidence that VLDL plays an important role in atherogenesis, in which plaques form on the interior walls of arteries, narrowing these passageways and restricting blood flow, which can lead to heart disease and increase the risk of stroke. Currently, direct measurement of VLDL cholesterol requires specialized testing. However, since VLDL-C contains most of the circulating triglyceride (if a person is fasting) and since the composition of the different particles is relatively constant, it is possible to estimate the amount of VLDL-C based on the triglyceride value. To estimate VLDL-C, divide the triglyceride value by 5 if the value is in mg/dL or divide by 2.2 if the value is in mmol/L. In most cases, this formula provides a good estimate of VLDL-C. However, this formula becomes less accurate with increased triglyceride levels when, for example, a person has not fasted before having blood drawn. The calculation is not valid when the triglyceride level is greater than 400 mg/dl (4.5 mmol/L) because other lipoproteins are usually present. In this situation, VLDL-C may be measured directly using specialized testing.
• Triglycerides. Triglycerides are the most common type of fat in your blood. Triglycerides come from food, and your body also makes them. When you eat, your body converts calories it doesn’t need into triglycerides, which are stored in fat cells. Triglycerides are fats that provide energy for your muscles. If you eat foods with a lot of saturated fat or carbohydrates, you will raise your triglyceride levels. High triglyceride levels are associated with several factors, including being overweight, eating too many sweets or drinking too much alcohol, smoking, being sedentary, or having diabetes with elevated blood sugar levels. Elevated triglycerides levels are thought to lead to a greater risk of heart disease, but scientists do not agree that high triglycerides alone are a risk factor for heart disease. Normal triglyceride levels vary by age and sex. People with high triglycerides often have a high total cholesterol level, including a high LDL (bad) cholesterol level and a low HDL (good) cholesterol level. Many people with metabolic syndrome or diabetes also have high triglyceride levels. Extremely high triglyceride levels (more than 1000 mg/dL) can lead to abdominal pain and a life-threatening disorder of the pancreas called pancreatitis. Factors that can contribute to elevated triglyceride levels:
  • Overweight or obesity
  • Insulin resistance or metabolic syndrome
  • Diabetes mellitus, especially with poor glucose control
  • Alcohol consumption, especially in excess
  • Excess sugar intake, especially from processed foods
  • High saturated fat intake
  • Hypothyroidism
  • Chronic kidney disease
  • Physical inactivity
  • Pregnancy (especially in the third trimester)
  • Inflammatory diseases (such as rheumatoid arthritis, systemic lupus erythematosus
  • Some medications may also increase triglycerides.

Your body naturally produces all the LDL (bad) cholesterol it needs. However, the genes you inherit and your lifestyle habits play a major role in your cholesterol levels. The most common cause of high cholesterol is an unhealthy lifestyle. An unhealthy lifestyle makes your body produce more LDL cholesterol than it needs. This can include:

• Unhealthy eating habits or unhealthy diet, such as eating lots of bad fats. One type, saturated fat, is found in some meats, dairy products, chocolate, baked goods, and deep-fried and processed foods. Eating a lot of foods high in saturated fats raises “bad” LDL cholesterol levels. Another type, trans fat, is in some fried and processed foods. Eating these fats can raise your LDL (bad) cholesterol. No more than 10% of your daily calories should come from saturated fats.
• Lack of physical activity, with lots of sitting and little exercise. This lowers your HDL (good) cholesterol.
• Smoking or exposure to tobacco smoke, which lowers HDL cholesterol, especially in women. It also raises your LDL cholesterol.
• Being overweight or obese.
• Stress may raise levels of certain hormones, such as corticosteroids. These can cause your body to make more cholesterol.
• Drinking too much alcohol (more than two drinks a day for men or one drink a day for women) can raise your total cholesterol level.
• Getting little or low-quality sleep has been linked to lower cardiovascular health.

Genetics may also cause people to have high cholesterol. For example, some people inherit genes from their mother, father or even grandparents that cause them to have too much cholesterol. This is called familial hypercholesterolemia (FH). The severity of familial hypercholesterolemia is related to the duration and degree of LDL cholesterol in the blood. Familial hypercholesterolemia is dangerous because it can cause premature atherosclerotic heart disease. If you have a family history of familial hypercholesterolemia or problems related to high cholesterol, get your cholesterol levels checked.

High cholesterol usually causes no signs or symptoms. Cholesterol travels through your blood silently. And it turns into atherosclerotic plaque (hardened deposits) silently. Plaque buildup is like someone tip-toeing on carpet. You might not see or notice its presence for a long time. You may have no symptoms until you have a heart attack or stroke. At that point, the plaque is like high heels on a hardwood floor. And it’s already caused serious damage to your body.

You can live for many years with high cholesterol and not even know it. That’s why it’s essential to get your cholesterol levels checked on a regular basis. If your cholesterol levels are too high (hyperlipidemia), that’s a red flag for you and your doctor. High cholesterol is a major risk factor for heart disease. But catching it early gives you a chance to make changes and get your cholesterol to a healthy level.

You can find out your cholesterol level with a cholesterol or lipid profile blood test. If you are concerned about your cholesterol level, talk to your doctor. You will need to stop eating for 10 to 12 hours before a cholesterol or lipid profile blood test, and the only liquid you may drink is water.

Lifestyle changes such as regular physical activity, losing excess weight, quitting if you smoke and healthy eating are the first line of defense against high cholesterol. Eating lots of fruit and vegetables, whole grains (especially oats), and beans and lentils can help lower your cholesterol. You can also help by losing weight, avoiding foods that are high in saturated fat, quitting smoking and being active. But, if you’ve made these important lifestyle changes and your cholesterol levels remain high, your doctor might recommend medication.

To reduce your risk with high cholesterol, it’s important to:

• Quit cigarette smoking.
• Do regular aerobic exercise.
• Identify and treat high blood pressure.
• Maintain a healthy weight.
• Diagnose and treat diabetes.
• Have a healthy diet.

High cholesterol is one of the major controllable risk factors for coronary heart disease, heart attack and stroke. If you have other risk factors such as smoking, high blood pressure or diabetes, your risk increases even more. The more risk factors you have and the more severe they are, the higher your overall risk.

Remember, making even modest changes now can help to prevent significant medical issues later. Do all you can to reduce your risk for the serious effects of heart attack and stroke.

Figure 6. Cholesterol molecular structure

Footnotes: A cholesterol molecule contains three major parts: 1) tetracyclic carbon ring (A, B, C and D) as the core of steroids, 2) polar hydroxyl (OH) group attached to ring A, and 3) short non-polar carbon chain attached to ring D ⁵¹, ⁵². All four rings (A, B, C and D) of the sterol group are in a trans conformation, making cholesterol a planner molecule. The double bond between C5 and C6 helps to keep the rigidity of cholesterol.

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Figure 7. Effects of dietary fat and carbohydrate on plasma cholesterol levels

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HDL cholesterol function

HDL transports harmful cholesterol from other parts of your body including your arteries back to your liver and HDL also serves many other functions including communication with cells and the inactivation of biohazards like bacterial lipopolysaccharides ¹⁹. These functions are exerted by entire HDL particles or distinct proteins or lipids carried by HDL rather than by its cholesterol cargo measured as HDL cholesterol ⁵⁵, ⁵⁶. As discussed earlier, high-density lipoproteins contain several other apolipoproteins in addition to apoA-I. The second most abundant HDL apolipoprotein is apoA-II, followed by apoA-IV, the C apolipoproteins, apoE and apoM. These apolipoproteins all contribute to HDL structural stability and, in some cases, HDL function. HDLs also transport a cargo of other proteins that potentially further impact on HDL function.

In addition to the aforementioned proteins that are predominantly associated with lipid metabolism, HDLs contain proteins that promote proteolysis (e.g. alpha-1-antitrypsin), preventing and stopping bleeding a process called hemostasis (alpha-2-HS-glycoprotein), immunity (e.g. the acute phase reactant SAA4), complement activation (e.g. complement C3), and inflammation (e.g. haptoglobin-related protein) ²². As the concentration of most HDL-associated proteins is lower than the plasma concentration of HDL particles, each protein can associate only with specific HDL particle subsets ⁵⁵. One notable example is the complex consisting of apoA-I, haptoglobin-related protein, and apoL1 by which haptoglobin-related protein provides the binding to Trypanosoma and the internalized apoL1 elicits the lysosomal swelling, ultimately killing Trypanosoma ⁵⁷. By contrast, the lipid composition of HDL particles is highly dynamic. ABCA1 fluxes glycerophospholipids and cholesterol from cell membranes, especially to lipid-free apoA-I as well as to small, lipid-poor HDL. Lecithin cholesterol acyl transferase (LCAT) generates cholesteryl esters and lysophosphatidylcholines by the transfer of sn-2 fatty acids from phosphatidylcholines to the 3-OH group of cholesterol. Endothelial lipase and hepatic lipase hydrolyse phosphatidylcholines and triglycerides of HDL, respectively, generating free fatty acids, lysophosphatidylcholines, and diacylglycerols, which also are bioactive molecules. Cholesteryl ester transfer protein (CETP) exchanges cholesteryl esters of HDL for triglycerides from apoB-containing lipoproteins and phospholipid transfer protein (PLTP) transfers phospholipids from apoB-containing lipoproteins to HDL as well as between different HDLs ⁵⁸. In addition, lipids are fluxed between HDL and cells and between HDL and other lipoproteins following concentration gradients or affinity. For example, unesterified cholesterol is readily accepted by HDL from both lipolysed triglyceride-rich lipoproteins (TGRLs) or cell membranes but also transferred from HDL to LDL or cells ⁵⁹, ⁶⁰.

In summary, HDLs exert multiple functions that protect the organism from chemical or biological harm or help to repair the tissue damage caused by noxious agents. HDLs do so by three principal mechanisms.

Figure 8. High density lipoprotein cholesterol functions and diseases

Footnotes: High density lipoproteins (HDL) exert multiple protective activities, essentially by three major mechanisms. HDLs, however, can lose their protective functions and even gain adverse functions in chronic diseases or during infections. U-shaped relationships between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low HDL cholesterol and extremely high HDL cholesterol levels associated with an increased risk of several diseases and mortality.

Abbreviations: LCAT = lecithin:cholesterol acyltransferase; CETP = cholesteryl ester transfer protein; PONI = paraoxonase 1; S1P = sphingosine-1-phosphate; ASCVD = atherosclerotic cardiovascular disease; LDL = low-density lipoprotein; SAA = serum amyloid A; OxPL = oxidized phospholipids

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Cholesterol transport

The most intensively investigated function of HDL is reverse cholesterol transport by carrying harmful cholesterol from other parts of your body including your arteries back to your liver. HDL formation is initiated by the secretion of lipid free apoA-I by the liver comprising about 70% of total apoA-I production ⁶¹ and the intestine comprising about 30% of total apoA-I production ⁶². This lipid free apoA-I interacts with the ATP-binding cassette transporter A1 (ABCA1) on peripheral cells, leading to the transfer of cholesterol and cellular phospholipids from the cell membrane to apoA-I (Figure 3). Through a series of intermediate steps, the lipidated apoA-I is progressively converted into discoidal pre-β-migrating HDL particles that consist of a phospholipid bilayer surrounded by two apoA-I molecules/particle ⁶³. Subsequently, the enzyme lecithin cholesterol acyltransferase (LCAT) mediates the esterification of cholesterol, converting discoidal pre-β-migrating HDL particles into α-migrating, spherical HDL particles with a central core of cholesteryl esters ⁶⁴ and two molecules of apoA-I. Small spherical HDL subsequently acquire additional free cholesterol that effluxes from peripheral cells via ABCA1 and ABCG1. Esterification of this newly acquired cholesterol by LCAT generates large HDL particles with three or more apoA-I molecules/particle. Furthermore, phospholipid transfer protein (PLTP) plays a vital role in the remodelling of HDL, by transferring phospholipids from chylomicrons and VLDL to HDL ⁶⁵. This transfer of phospholipids can destabilize HDL, leading to fusion and the formation of larger α-migrating HDL particles ⁶⁶. Spherical HDL particles can also undergo modification through bi-directional exchange of cholesteryl esters and triglycerides with apoB containing lipoproteins (VLDL and LDL) mediated by cholesteryl ester transfer protein (CETP). As CETP predominately supports the transfer of cholesteryl esters from HDL towards apoB containing lipoproteins in exchange for triglycerides, this process will result in triglyceride–rich HDL ⁶⁷, ⁶⁸. The exact mechanism of the HDL-CETP interactions remains part of active research, as some studies suggest that CETP bind to HDL by hydrophobic interaction whereas others suggest it is rather a protein-protein interactions ⁶⁹. The formation of a hydrophobic channel by SR-B1, allowing cholesterol diffusion from HDL into the plasma membrane, can further remodel HDL ⁷⁰. Additionally, hepatic lipase can hydrolyse HDL phospholipids and triglycerides, driving the transition of HDL2 into HDL3 particles ⁷¹. This remodelling is accompanied by the dissociation of lipid-free or lipid-poor apoA-I, while endothelial lipase remodels HDL without such dissociation ⁷². In the kidney, this lipid-free apoA-I undergoes glomerular filtration and can subsequently either be degraded, excreted through the urine or partially reabsorbed, thereby regulating the plasma levels of apoA-I and HDL ⁷³, ⁷⁴.

HDL Antioxidant properties

HDLs reduce oxidative stress in low density lipoproteins (LDLs) and other atherogenic lipoproteins by accepting lipid hydroperoxides and detoxifying them into lipid hydroxides that are cleared from the circulation by the liver ²². Small HDLs inhibit oxidation more effectively than large HDLs ⁷⁵. This can potentially negate, the reduced cardioprotection that is associated with low plasma HDL levels ²². It also raises the possibility that treatment with drugs that increase the level of large HDLs may not improve the antioxidant properties of HDLs ²².

Paraoxonase1 (PON1) and platelet-activating factor acetyl hydrolase (PAF-AH) contribute to the antioxidant properties of HDLs independent of reducing lipid hydroperoxides to hydroxides ²². Although paraoxonase1 (PON1) knockout mice are atherosclerosis-prone, and overexpression of human PON1 reduces atherosclerosis in mice ⁷⁶, ⁷⁷, the mechanism by which PON1 inhibits oxidation, and its impact on atherosclerotic lesion development, is not well understood. The mechanism of the antioxidant properties of platelet-activating factor acetyl hydrolase (PAF-AH) have been elucidated, and include the hydrolysis of oxidised fatty acid constituents in phospholipids. However, the precise contribution of platelet-activating factor acetyl hydrolase (PAF-AH) to the antioxidant properties of HDLs requires further clarification. Interventions that exploit these cardioprotective functions of HDLs have yet to be developed.

HDL Anti-diabetic properties

HDLs and HDL apolipoproteins improve glycemic control in animal models of diabetes by enhancing pancreatic Beta-cell function and survival and improving insulin sensitivity ⁷⁸. HDLs also inhibit Beta-cell apoptosis and protect Beta-cells from oxidation by low-density lipoproteins (LDLs) ⁷⁹, ⁸⁰.

Evidence that the anti-diabetic functions of HDLs are clinically relevant has emerged from a meta-analysis of all cholesteryl transfer protein (CETP) inhibitor trials showing a 12% reduction in incident diabetes ⁸¹. A more detailed in analysis of dalcetrapib revealed that the reduced incidence in diabetes may be a consequence of the treatment-related increase in HDL cholesterol but not change in body mass index (BMI) and regression from diabetes to no diabetes ⁸². These studies provided the first direct evidence that increasing HDL levels may reduce cardiometabolic risk. Identification of specific HDL subpopulations that mediate these effects would enable this approach to be further developed treatments to increasing a specific HDL particle.

HDL Anti-inflammatory properties

Inflammation is a key driver of chronic diseases such as atherosclerotic cardiovascular disease and diabetes as well as infections and malignancies. HDLs directly affect the inflammatory process and HDLs reduce inflammation in multiple cell types, including endothelial cells and macrophages ⁸³, ⁸⁴, ⁸⁵. In endothelial cells HDLs inhibit inflammation by reducing activation of nuclear factor-κB (NF-κB) and 3β-hydroxysteroid-Δ24 reductase, by activating the cytoprotective enzyme, heme oxygenase-1 and by inhibiting inflammasome activation ⁸⁶, ⁸³. HDLs exert these effects by several mechanisms including the interaction of HDL-associated apoM/sphingosine-1-phosphate (S1P) with S1P receptors ⁸⁷. They also reduce inflammation in monocytes and attenuate the binding of monocytes to adhesion molecules on the surface of activated endothelial cells ⁸⁷, ⁸⁸.

Approximately ~90-95% of the apoA-I in plasma is bound to HDL particles, but pro-inflammatory states can cause it to dissociate into the circulation in a lipid-free or lipid-poor form ⁸⁹. The role of HDLs and apoA-I in macrophage inflammation, a key driver of atherosclerotic lesion progression, has been investigated extensively.8, 10, 19–25, 27 While early studies focused on the anti-inflammatory effects of HDLs ⁸³, ⁸⁸, ⁸⁴, ⁹⁰, ⁹¹, ⁸⁵, ⁹², more recent studies showing that HDLs and apoA-I can also be pro-inflammatory ⁹⁰, ⁹³, ⁹⁴ may be one explanation for the limited success of HDL-raising drugs in reducing atherosclerotic cardiovascular disease. However, the pro-inflammatory effects of HDLs could be beneficial in other diseases, such as sepsis, where enhanced inflammation may promote efficient clearance of bacteria ⁹⁴. Understanding the mechanistic links between HDLs and their role in inflammation is vital for understanding the prognostic and therapeutic potential of high-density lipoprotein class.

Whether HDLs and apoA-I are pro- or anti-inflammatory depends on several structural or functional features, including HDL composition, macrophage cholesterol content and signalling pathways ⁸⁴, ⁹⁰, ⁹³. Macrophages produce pro- and anti-inflammatory cytokines. Production of pro-inflammatory cytokines occurs downstream of Toll-like receptors (TLRs) that are activated by components of viruses or bacteria. The best known examples of this is are lipopolysaccharide (LPS) that activates TLR4, and lipoteichoic acid (LTA) that activates Toll-like receptor 2 (TLR2) ⁹⁵. While HDLs and apoA-I suppress inflammation by binding directly to and neutralising lipopolysaccharide (LPS) or lipoteichoic acid (LTA), they also affect Toll-like receptor (TLR) activation and downstream signalling pathways directly ⁹⁵.

Communication with cells

HDLs regulate the differentiation, proliferation, migration, survival, and function of many cell types. HDLs modulate the inflammatory action of innate and adaptive immune cells ⁹⁶, support the integrity and functionality of endothelial barriers, stimulate angiogenesis ⁹⁷ and secure energy homeostasis by stimulating insulin synthesis and secretion by pancreatic beta cells as well as glucose uptake by adipocytes and myocytes ⁷⁸. Principally, these cellular responses result from either altered cholesterol homeostasis due to fluxes of cholesterol between cells and HDL, specific molecular interactions between HDL and cells, or combinations thereof.

First, cholesterol efflux alters the cholesterol content of specific plasma membrane domains, so-called rafts, that are enriched with signalling molecules, resulting in different effects depending on the cell type. Examples are the activation of endothelial nitric oxide synthase (eNOS) by HDL/SR-BI interaction in caveolae of endothelial cells ⁹⁸ as well as the dampening of toll-like receptor-4 response in monocytes ⁸⁴ or T-cell receptor signalling in lymphocytes ⁹⁹; cholesterol efflux also alters the transcription of sterol-regulated genes ¹⁰⁰.

Second, the interactions of HDL with SR-BI or apoA-I with ABCA1 induce signal transduction via the recruitment of intracellular proteins, which in turn activate different cellular responses such as eNOS activation in endothelial cells or glucose uptake into myocytes ¹⁰¹, ¹⁰².

Third, HDLs transport agonists of specific signalling receptors; the interaction of S1P with S1P receptors activates diverse signalling cascades and results in many protective effects on endothelial functions, including the induction of nitric oxide (NO) production and the maintenance of the endothelial barrier integrity ⁹⁷, ¹⁰³. Furthermore, S1P facilitates the trans-endothelial transport of HDL and thereby entry into extravascular tissues and spaces, where HDL exerts its protective activities ¹⁰⁴. S1P also modulates inflammatory effects on macrophages and lymphocytes and promotes the survival of hearts and kidneys exposed to hypoxia, ischemia-reperfusion injury, or toxic drugs ¹⁰³.

Fourth, HDLs deliver cargo into cells either by selective uptake, i.e. independently of the entire particle, or via holoparticle uptake ¹⁰⁵. SR-BI mediates the selective uptake not only of lipids but also microRNAs (miR) carried by HDL ¹⁰⁶. HDL-holoparticle uptake in the liver plays an important role in the metabolism of HDL ¹⁰⁷. In addition, monocyte-derived macrophages and enterocytes also internalize entire HDL particles, but the mechanism or the consequence of this is not understood ¹⁰⁸, ¹⁰⁹.

In summary, HDLs elicit a plethora of cellular responses by employing several modes of communication. Some mechanisms, for example, S1P receptor activation or cholesterol efflux, lead to many diverse responses in different cell types. Vice versa, identical responses can be evoked by several modes of action.

Inactivation of biohazards

By its amphiphilic structure and its cycling between extravascular and intravascular compartments, HDLs bind potentially toxic substances, such as bacterial lipopolysaccharides, oxidized lipids, as well as some lipophilic xenobiotics ¹¹⁰, ¹¹¹. In plasma, potentially hazardous molecules are either eliminated by reverse transport to the liver or inactivated directly on the surface of HDLs. The best-investigated example for the latter situation is the hydrolysis of oxidized phospholipids by paraoxonase 1, lipoprotein-associated phospholipase A2, and LCAT ¹¹², ¹¹³, ¹¹⁴. HDLs also exert direct antimicrobial effects on viruses and even protozoa ⁵⁷, ¹¹¹, ¹¹⁵. At least in vitro, HDL or apoA-I interfere with the entry or fusion of viruses with target cells (Pirillo A, Catapano AL, Norata GD. HDL in infectious diseases and sepsis. Handb Exp Pharmacol. 2015;224:483-508. doi: 10.1007/978-3-319-09665-0_15)). Of note, SR-BI is an entry route of several viruses into cells ¹¹⁶ and this process may be competed by HDLs ¹¹⁷.

Finally, HDLs is enriched with proteases and protease inhibitors which modulate platelet aggregation, coagulation, fibrinolysis, complement activation, and tissue degradation. They help to counteract downstream adverse effects of injuries, infections, and inflammation and support wound healing ¹¹⁸. Of note, functionally related proteins tend to cluster within distinct sub-populations of HDL ³³, ³⁴.

Effects of dietary fat on high density lipoprotein

Most studies of diet and HDL have focused on the effect of dietary macronutrients – carbohydrate, fat, and protein – on HDL-cholesterol levels. Dietary fat when it replaces carbohydrate increases HDL-cholesterol

Saturated, monounsaturated, and n−6 polyunsaturated fats have this effect (Fig. ​(Fig.1),1), saturated more so than monounsaturated or polyunsaturated fat [1,2]. Carbohydrate lowers HDL-cholesterol by about 5 mg/dL per 10 percentage points of total daily calories exchanged with fat [2]. The HDL-cholesterol lowering effect of carbohydrate occurs whether the carbohydrate is refined or whole grain, or low or high glycemic index [3]. Because fat and carbohydrate are macronutrients, supplying energy, another reference point is needed to determine direct effects of increasing dietary fat. Using protein as the reference, dietary fat replacing protein raises HDL-cholesterol even more than fat replacing carbohydrate [4]. Therefore, it is fair to conclude that dietary fat directly increases HDL-cholesterol regardless of whether it replaces carbohydrate or protein. However, the metabolic basis is not well established.

 

 

What can you do if your HDL cholesterol is Low?

If your HDL levels is low, you can take several steps to boost your HDL level and reduce your heart disease risk ¹¹⁹:

• Get physically active or exercise – Aerobic exercise for 30 to 60 minutes on most days of the week can help pump up your HDL levels. Some studies suggest that physical activity can raise HDL cholesterol. The American Heart Association recommends three to four 40-minute sessions of moderate- to vigorous-intensity aerobic activity per week for adults trying to lower their LDL cholesterol or blood pressure.
• Eat better fats. The monounsaturated and polyunsaturated fats described above can raise HDL cholesterol levels.
• Cut out trans fats. Not only do they increase LDL cholesterol, they decrease HDL cholesterol too.
• Quit smoking – Tobacco smoke lowers HDL, and quitting can increase HDL levels.
• Keep a healthy weight –  Being overweight increases LDL cholesterol and reduces HDL cholesterol levels. Losing even a few pounds will increase your HDL-C and lower your LDL-C and blood pressure. Avoiding obesity besides improving HDL levels, reduces risk for heart disease and multiple other health conditions.

What is LDL cholesterol?

LDL (“bad”) cholesterol can contribute to the formation of plaque buildup in the arteries (atherosclerosis). This is linked to higher risk for heart attack and stroke.

You want your LDL below 70 milligrams per deciliter (mg/dl).

If you have high LDL or total cholesterol, you can lower your risk of heart disease by:

• Stop smoking if you smoke
• Maintaining a healthy weight
• Avoid foods high in saturated fat, dietary cholesterol, and extra calories
• Limiting your alcohol and salt intake
• Exercise for at least 30 minutes on most days
• Managing stress.

High low density lipoprotein (LDL) cholesterol

Anyone can develop high cholesterol. High cholesterol can be caused by many different things; some you can control, and others you can’t.

• Your lifestyle:
  • Eating too much saturated fat – this reduces the liver’s ability to remove cholesterol, so it builds up in the blood
  • Being physically inactive – being active raises the level of ‘good’ cholesterol and reduces the level of ‘bad’ cholesterol
  • Smoking - this can lead to high cholesterol levels, reduce your HDL (good) cholesterol and it causes tar to build up in your arteries, making it easier for cholesterol to stick to your artery walls.
• Your age, biological sex and ethnic background:
  • getting older – having higher cholesterol is more likely as we age
  • male – males are more likely to have high cholesterol
  • ethnic background – if you are from a south Asian background, you are more likely to have high cholesterol.
• Your genes. Genes carry the information that determine your features or characteristics that are passed on to you — or inherited — from your parents.
  • Familial hypercholesterolemia (FH), is an inherited condition, meaning you were born with it. It’s often passed down through families in faulty genes and can lead to very high levels of cholesterol, even if you do not have other risk factors.
  • Familial combined hyperlipidemia
  • Familial dysbetalipoproteinemia
  • Familial hypertriglyceridemia
  • Lipoprotein-A also called lipoprotein (a), or LP(a), is made in your liver and carries fats around the body. High Lipoprotein-A is a condition that can cause heart problems like heart attack and stroke. This is because Lipoprotein-A is ‘sticky’ and can build up in your arteries. It’s usually an inherited condition but there are other causes.
• Your general health:
  • Kidney disease – when your kidneys aren’t working well, it also changes the way your body handles cholesterol, which can lead to high cholesterol
  • Liver disease – an important job of the liver is to both produce cholesterol and clear it from the body, but if the liver isn’t working well it struggles to do this, increasing your risk of high cholesterol
  • Being overweight, especially with excess fat around your middle
  • Type 2 diabetes put you at greater risk of having high cholesterol
  • Polycystic ovary syndrome (PCOS)
  • Pregnancy and other conditions that increase levels of female hormones
  • Sleep apnea
  • Having an underactive thyroid (hypothyroidism – when your body doesn’t make enough thyroid hormone)
  • Growth hormone deficiency (when not enough of the growth hormone is made).

For people with conditions such as lupus and HIV, the condition itself and the medicine used to treat it may lead to unhealthy cholesterol levels.

Medicines such as certain birth control pills, diuretics (water pills), beta-blockers, and some medicines used to treat depression may also raise cholesterol levels.

Some medicines that you take for other health problems can raise your level of “bad” LDL cholesterol or lower your level of “good” HDL cholesterol, including:

• Arrhythmia medicines, such as amiodarone
• Beta-blockers for relieving angina chest pain or treating high blood pressure
• Chemotherapy medicines used to treat cancer
• Diuretics, such as thiazide, to treat high blood pressure
• Immunosuppressive medicines, such as cyclosporine, to treat inflammatory diseases or to prevent rejection after organ transplant
• Retinoids to treat acne
• Steroids, such as prednisone, to treat inflammatory diseases such as lupus, rheumatoid arthritis, and psoriasis

Risk factors for developing high cholesterol

Factors that can increase your risk of bad cholesterol include:

• Poor diet. Eating saturated fat, found in animal products, and trans fats, found in some commercially baked cookies and crackers and microwave popcorn, can raise your cholesterol level. Foods that are high in cholesterol, such as red meat and full-fat dairy products, will also increase your cholesterol.
• Age. Your cholesterol levels tend to rise as you get older. For instance, as you age, your liver becomes less able to remove LDL cholesterol. Even though it is less common, younger people, including children and teens, can also have high cholesterol.
• Sex. Between ages 20 and 39, men have a greater risk for high total cholesterol than women. A woman’s risk goes up after menopause. Menopause lowers levels of female hormones that may protect against high blood cholesterol. After menopause, women’s levels of total and “bad” LDL cholesterol usually go up, while their levels of “good” HDL cholesterol go down.
• Heredity. High blood cholesterol can run in families.
• Weight. Being overweight or having obesity raises your cholesterol level. Having a body mass index (BMI) of 30 or greater puts you at risk of high cholesterol.
• Race. Certain races may have an increased risk of high cholesterol.
  • Overall, non-Hispanic White people are more likely than other groups to have high levels of total cholesterol.
  • Asian Americans, including those of Indian, Filipino, Japanese, and Vietnamese descent, are more likely to have high levels of “bad” LDL cholesterol than other groups.
  • Hispanic Americans are more likely to have lower levels of “good” HDL cholesterol than other groups.
  • African Americans are more likely than other groups to have high levels of “good” HDL cholesterol.
• Lack of exercise. Being physically inactive contributes to overweight and can raise LDL and lower HDL. Exercise helps boost your body’s HDL, or “good,” cholesterol while increasing the size of the particles that make up your LDL, or “bad,” cholesterol, which makes it less harmful.
• Smoking. Cigarette smoking damages the walls of your blood vessels, making them more prone to accumulate fatty deposits. Smoking might also lower your level of HDL, or “good,” cholesterol.
• Diabetes. High blood sugar contributes to higher levels of a dangerous cholesterol called very-low-density lipoprotein (VLDL) and lower HDL cholesterol. High blood sugar also damages the lining of your arteries.

How to lower LDL cholesterol

You can lower your LDL cholesterol level by adopting a heart-healthy lifestyle changes. They include eating a healthy diet, weight management, and regular physical activity.

• Choose heart-healthy foods. The DASH eating plans can help you lower your “bad” LDL cholesterol. These plans encourage:
  • Limiting saturated fats found in fatty cuts of meats, dairy products, and desserts
  • Eating whole grains, fruits, and vegetables rather than refined carbohydrates such as sweets and other high-sugar foods
  • Eating a variety of nuts
  • Preparing foods with little or no salt
• Get regular physical activity. Studies have shown that physical activity can lower LDL “bad” cholesterol and triglycerides and raise your “good” HDL cholesterol. For example, resistance training among postmenopausal women may decrease total cholesterol, LDL cholesterol, and triglycerides. Before starting any exercise program, ask your provider what level of physical activity is right for you.
• Aim for a healthy weight. Research has shown that adults with overweight and obesity can lower “bad” LDL cholesterol and raise “good” HDL cholesterol by losing only 3% to 5% of their weight.
• Manage stress. Research has shown that chronic stress can sometimes increase LDL cholesterol levels and decrease HDL cholesterol levels.
• Quit smoking. If you smoke, quit. Smoking can raise your risk of heart disease and heart attack and worsen other heart disease risk factors. Talk with your doctor about programs and products that can help you quit smoking. Also, try to avoid secondhand smoke.
• Get enough good quality sleep. Getting 7 to 9 hours of sleep a day lowers your risk for high “bad” cholesterol (LDL) and total cholesterol.
• Limit alcohol. Visit the National Institute on Alcohol Abuse and Alcoholism for resources on support and treatment to stop drinking.

If your healthy lifestyle changes alone do not lower your cholesterol enough, you may also need to take medicines. There are several types of cholesterol-lowering drugs available, including statins. If you take medicines to lower your cholesterol, you still should continue with the lifestyle changes.

Some people with familial hypercholesterolemia (FH) may receive a treatment called lipoprotein apheresis. This treatment uses a filtering machine to remove LDL cholesterol from the blood. Then the machine returns the rest of the blood back to the person.

Eating a heart-healthy diet

From a dietary standpoint, the best way to lower your cholesterol is reduce your intake of saturated fat, trans fat and cholesterol. The American Heart Association recommends limiting saturated fat to less than 6% of daily calories and minimizing the amount of trans fat you eat.

Reducing these fats means limiting your intake of red meat and dairy products made with whole milk. Choose skim milk, low-fat or fat-free dairy products instead. It also means limiting fried food and cooking with healthy oils, such as vegetable oil.

A heart-healthy diet emphasizes fruits, vegetables, whole grains, poultry, fish, nuts and nontropical vegetable oils, while limiting red and processed meats, sodium and sugar-sweetened foods and beverages.

Many diets fit this general description. For example, the DASH (Dietary Approaches to Stop Hypertension) eating plan promoted by the National Heart, Lung, and Blood Institute as well as diets suggested by the U.S. Department of Agriculture and the American Heart Association are heart-healthy approaches. Such diets can be adapted based on your cultural and food preferences.

Becoming more physically active

A sedentary lifestyle lowers HDL cholesterol. Less HDL means there’s less good cholesterol to remove bad cholesterol from your arteries.

Physical activity is important. At least 150 minutes of moderate-intensity aerobic exercise a week is enough to lower both cholesterol and high blood pressure. And you have lots of options: brisk walking, swimming, bicycling or even yard work can fit the bill.

Quitting smoking

Smoking and vaping lowers HDL cholesterol.

Worse still, when a person with unhealthy cholesterol levels also smokes, risk of coronary heart disease increases more than it otherwise would. Smoking also compounds the risk from other risk factors for heart disease, such as high blood pressure and diabetes.

By quitting, smokers can lower their LDL cholesterol and increase their HDL cholesterol levels. It can also help protect their arteries. Nonsmokers should avoid exposure to secondhand smoke.

Losing weight

Being overweight or obese tends to raise bad cholesterol and lower good cholesterol. But a weight loss of as little as 5% to 10% can help improve cholesterol numbers. Losing even 5 to 10 pounds can help lower cholesterol levels.

Manage stress

Research has shown that chronic stress can sometimes raise your LDL cholesterol and lower your HDL cholesterol. Try to reduce your stress. You can do that by deep breathing and relaxation techniques. Examples include meditation and gentle exercise (such as walking or yoga). Also talking with a friend, family member, or health care professional may be helpful.

Medications for high cholesterol

Your doctor might suggest medication to help keep your cholesterol in the healthy range. The choice of medication or combination of medications depends on various factors, including your personal risk factors, your age, your health and possible drug side effects. Common choices include:

• Statins. Statins block a substance your liver needs to make cholesterol. This causes your liver to remove cholesterol from your blood. Statins can also help your body reabsorb cholesterol from built-up deposits on your artery walls, potentially reversing coronary artery disease. Choices include atorvastatin (Lipitor), fluvastatin (Lescol XL), lovastatin (Altoprev), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor). The common side effects of statins are muscle pains and muscle damage, reversible memory loss and confusion, and elevated blood sugar.
• Bile-acid-binding resins. Your liver uses cholesterol to make bile acids, a substance needed for digestion. The medications cholestyramine (Prevalite), colesevelam (Welchol) and colestipol (Colestid) lower cholesterol indirectly by binding to bile acids. This prompts your liver to use excess cholesterol to make more bile acids, which reduces the level of cholesterol in your blood.
• Cholesterol absorption inhibitors. Your small intestine absorbs the cholesterol from your diet and releases it into your bloodstream. The drug ezetimibe (Zetia) helps reduce blood cholesterol by limiting the absorption of dietary cholesterol. Ezetimibe can be used with a statin drug.
• Bempedoic acid. This newer drug works in much the same way as statins but is less likely to cause muscle pain. Adding bempedoic acid (Nexletol) to a maximum statin dosage can help lower LDL significantly. A combination pill containing both bempedoic acid and ezetimibe (Nexlizet) also is available.
• Bile-acid-binding resins. Your liver uses cholesterol to make bile acids, a substance needed for digestion. The medications cholestyramine (Prevalite), colesevelam (Welchol) and colestipol (Colestid) lower cholesterol indirectly by binding to bile acids. This prompts your liver to use excess cholesterol to make more bile acids, which reduces the level of cholesterol in your blood.
• Injectable medications. A newer class of drugs, known as PCSK9 inhibitors, can help the liver absorb more LDL cholesterol — which lowers the amount of cholesterol circulating in your blood. Alirocumab (Praluent) and evolocumab (Repatha) might be used for people who have a genetic condition that causes very high levels of LDL or in people with a history of coronary disease who have intolerance to statins or other cholesterol medications. PCSK9 inhibitors are injected under the skin every few weeks and are expensive.

If you also have high triglycerides, your doctor might prescribe:

• Fibrates. Fibrates mostly lower triglycerides and, to a lesser degree, raise HDL levels. Fibrates are less effective in lowering LDL levels. The medications fenofibrate (Tricor, Fenoglide, others) and gemfibrozil (Lopid) reduce your liver’s production of very-low-density lipoprotein (VLDL) cholesterol and speed the removal of triglycerides from your blood. VLDL cholesterol contains mostly triglycerides. Using fibrates with a statin can increase the risk of statin side effects.
• Nicotinic acid also called niacin or vitamin B3. Niacin is the generic name for nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (niacinamide or pyridine-3-carboxamide), and related derivatives, such as nicotinamide riboside ¹²⁰. Niacin is a water-soluble B3 vitamin that should be taken only under physician supervision. Niacin limits your liver’s ability to produce LDL and VLDL cholesterol. It improves all lipoproteins—total cholesterol, LDL, triglycerides, and HDL—when taken in doses well abovethe vitamin requirement. But niacin doesn’t provide additional benefits over statins. Niacin has also been linked to liver damage and strokes, so most doctors now recommend it only for people who can’t take statins.
• Omega-3 fatty acid supplements. Omega-3 fatty acid supplements can help lower your triglycerides. They are available by prescription or over-the-counter. If you choose to take over-the-counter supplements, get your doctor’s OK. Omega-3 fatty acid supplements could affect other medications you’re taking.

If you are on such medication, you might need regular cholesterol tests to check that they are working well and that you are taking the right dose. If you decide to take cholesterol medication, your doctor might recommend liver function tests to monitor the medication’s effect on your liver.

Experts from the National Cholesterol Education Program (NCEP) say that more aggressive cholesterol treatment is needed for people at high risk of dying from a heart attack or cardiovascular disease. The basic message of the group’s recommendations is the lower the better when it comes to levels of low-density lipoprotein (LDL) or “bad cholesterol”. The updated recommendations say that almost all high-risk patients with LDL cholesterol levels of 100 mg/dL or higher should begin taking cholesterol-lowering medicine.

Lipoprotein apheresis

Some people with familial hypercholesterolemia may benefit from lipoprotein apheresis to lower their blood cholesterol levels. Lipoprotein apheresis uses a filtering machine to remove unwanted substances from the body. The machine removes “bad” LDL cholesterol from the blood, then returns the remainder of the blood to your body.

Alternative medicine

Few natural products have been proved to reduce cholesterol, but some might be helpful. With your doctor’s OK, consider these cholesterol-lowering supplements and products:

• Barley
• Plant sterols and stanols, found in oral supplements, some fortified orange juices and some margarines, such as Promise Activ
• Blond psyllium, found in seed husk and products such as Metamucil
• Oat bran, found in oatmeal and whole oats

Another popular cholesterol-lowering supplement is red yeast rice. There is evidence that red yeast rice can help lower your LDL cholesterol. Some red yeast rice products contain substances called monacolins, which are produced by the yeast. However, the U.S. Food and Drug Administration (FDA) has said that red yeast rice products that contain monacolin K, a naturally occurring form of the prescription cholesterol-lowering drug lovastatin and can cause the same types of side effects and drug interactions as lovastatin, cannot be sold legally as dietary supplements in the United States. Other red yeast rice products contain little or no monacolin K, and it is not known whether these products have any effect on cholesterol levels. Unfortunately, there is no way to know how much monacolin K is present in most red yeast rice products.

If you buy red yeast rice supplements in the United States, there’s no way to know whether you’re getting enough monacolin K to lower your LDL cholesterol. In other countries, lovastatin in red yeast rice products is potentially dangerous because there’s no way to know how much might be in a particular product or what the quality of the lovastatin is.

• Flaxseed. Studies of flaxseed preparations to lower cholesterol levels report mixed results. A 2009 review of the scientific research of flaxseed for lowering cholesterol found modest improvements in cholesterol, seen more often in postmenopausal women and in people with high initial cholesterol concentrations.
• Garlic. Some evidence indicates that taking garlic supplements can slightly lower blood cholesterol levels. A recent review of the research on garlic supplements concluded that they can lower cholesterol if taken for more than 2 months, but their effect is modest in comparison with the effects of cholesterol-lowering drugs. However, a National Center for Complementary and Integrative Health-funded study on the safety and effectiveness of three garlic preparations (fresh garlic, dried powdered garlic tablets, and aged garlic extract tablets) for lowering blood cholesterol levels found no effect. Although garlic supplements appear to be safe for most adults, they can thin the blood in a manner similar to aspirin, so use caution if you are planning to have surgery or dental work. Garlic supplements have also been found to interfere with the effectiveness of saquinavir, a drug used to treat HIV infection.
• Some soy products can have a small cholesterol-lowering effect. An analysis of data from 35 studies indicated that soy foods were more effective in lowering cholesterol than soy protein supplements and that isoflavones (substances in soy that have a weak estrogenic effect) did not lower cholesterol. The effect of soy is much smaller than that of cholesterol-lowering drugs.
• Limited evidence indicates that green tea may have a cholesterol-lowering effect. The evidence on black tea is less consistent.
• Chromium, vitamin C, artichoke extract, the herb Hibiscus sabdariffa, coenzyme Q10, and selenium have been studied for cholesterol but have not been found to be effective. Research findings don’t show clear evidence regarding the cholesterol-lowering effects of policosanol (derived from sugar cane) and guggulipid (from the mukul mirth tree in western India).

Even if you take cholesterol-lowering supplements, remember the importance of a healthy lifestyle, and take medication to reduce your cholesterol as directed. Tell your doctor which supplements you take.

High cholesterol

High cholesterol also called hypercholesterolemia, hyperlipidemia or lipid disorder (dyslipidemia) is when you have too much “bad cholesterol” [too much non-HDL cholesterol and LDL (bad) cholesterol] in your blood, which can increase your risk of having a heart attack, stroke and other atherosclerotic cardiovascular disease ¹²¹. A stroke occurs when a blood clot blocks blood flow to part of your brain. If you have too much cholesterol in your blood, it can combine with other substances in the blood to form plaque. Plaque sticks to the walls of your arteries. This buildup of plaque is known as atherosclerosis. It can lead to coronary artery disease, where your coronary arteries become narrow or even completely blocked, which can cause a heart attack (myocardial infarction). A heart attack occurs when your heart muscle tissue does not receive vital oxygen and nutrients. Atherosclerosis (buildup of plaque in arteries) is the process that causes the artery wall to get thick and stiff. The disease process begins when LDL (“bad” cholesterol) deposits cholesterol in the artery wall. Your body has an immune response to protect itself and sends white blood cells called macrophages to engulf the invading cholesterol in the artery wall. When the macrophages are full of cholesterol, they are called foam cells because of their appearance. As more foam cells collect in the artery wall, a fatty streak develops between the intima and the media. If the process is not stopped, the fatty streak becomes a plaque, which pushes the intima into the lumen, narrowing the blood flow. The plaque develops a fibrous coating on its outer edges. But if cholesterol continues to collect in foam cells inside the plaque, the fibrous outer coating can weaken and eventually rupture. Smaller arteries downstream from the rupture can quickly become blocked. Over time, a clot may develop at the rupture site and completely block the artery.

Evidence shows that the atherosclerotic process begins in childhood and progresses slowly into adulthood. Later in life, this often leads to coronary heart disease, the leading cause of death in the United States.

Cholesterol comes from two sources. Your liver makes all of the cholesterol your body needs to form cell membranes and to make certain hormones. Cholesterol is also found in foods from animal sources, such as egg yolks, meat, and cheese, which is called dietary cholesterol. Although we often blame the cholesterol found in foods that we eat for raising blood cholesterol, the main culprit is actually saturated fat. Foods rich in saturated fat include butter fat in milk products, fat from red meat, and tropical oils such as coconut oil.

There are usually no symptoms of high cholesterol. But if left untreated, it can lead to heart attack and stroke.

High cholesterol is often a hidden risk factor which means it can happen without us knowing until it’s too late. Undiagnosed or untreated high blood cholesterol can lead to serious problems, such as heart attack and stroke. That is why it’s so important to get your cholesterol level checked. Talk to your doctor about your risk and steps you can take to keep your cholesterol levels in a healthy range.

Cholesterol can enter your artery wall, damage its integrity and lead to the formation of atherosclerotic plaque (hardened deposits). This process of plaque buildup is called atherosclerosis. It can lead to serious problems like:

• Coronary artery disease: Blocked blood flow to your heart.
• Peripheral artery disease: Blocked blood flow to your legs and arms.
• Carotid artery disease: Blocked blood flow to your brain.

Cholesterol levels

Your cholesterol levels show how much cholesterol is circulating in your blood. Your blood cholesterol levels tell you how much lipid or fat is in your blood and your cholesterol levels are expressed in milligrams per deciliter (mg/dL).

Total blood or serum cholesterol is a composite of different measurements. Your “total blood cholesterol” is calculated by adding your HDL (“good” cholesterol) and LDL (“bad” cholesterol) cholesterol levels, plus 20% of your triglyceride level.

The formula for calculating your “total blood cholesterol”: Total cholesterol = HDL + LDL + 20% triglycerides.

• “Total cholesterol” is the total amount of cholesterol that’s circulating in your blood. Your “Total cholesterol” should be below 200 milligrams per deciliter of blood (mg/dL) or 5.18 mmol/L.
• Your HDL “good” cholesterol is the one number you want to be high, ideally above 60 mg/dL (1.55 mmol/L) or higher.
• Your LDL “bad” cholesterol should be below 100 mg/dL (less than 2.59 mmol/L).
• Your triglycerides should be below 150 mg/dL (less than 1.70 mmol/L). Triglycerides are the most common type of fat in your blood. Triglycerides come from food, and your body also makes them. When you eat, your body converts calories it doesn’t need into triglycerides, which are stored in fat cells. High triglyceride levels are associated with several factors, including being overweight, eating too many sweets or drinking too much alcohol, smoking, being sedentary, or having diabetes with elevated blood sugar levels.
• Talk with your doctor about what your results mean for you and how to manage your cholesterol.

“Normal cholesterol levels” are less important than your overall cardiovascular risk. Like HDL and LDL cholesterol levels, your total blood cholesterol level should be considered in context with your other known risk factors. To determine your cardiovascular risk, your doctor will consider your cholesterol test results in context with your age, sex and family history. Other risk factors, such as smoking, diabetes and high blood pressure, will be considered as well. If your risk remains uncertain, and treatment options are unclear, your doctor may consider other factors and/or request a coronary artery calcium measurement to provide greater insight into your risk and help in decision-making.

In general, you want to have a total cholesterol level below 200 mg/dL or 5.18 mmol/L. Between 200 mg/dL and 239 mg/dL, your cholesterol level is elevated or borderline-high and should be lowered if you can. With a total cholesterol level of 240 mg/dL or above, your cholesterol level is high, and there is a need for action. For example, changing your diet, beginning an exercise program, and taking statins or other cholesterol-lowering medicines are all ways to lower your cholesterol level.

A decision about needing medication for high cholesterol is based on all your risk factors, not just the cholesterol. A cardiovascular risk assessment predicts your risk of heart attack or stroke in the next 10 years. A free online computer programme that predicts it is called QRISK, so you may hear your doctor talk about a ‘QRISK score’. If it suggests a 10 per cent risk or higher, you may be offered dietary advice and drug treatment (usually a statin) to help lower your cholesterol. The treatment is usually long-term. Increasingly, we are looking at an individual’s lifetime risk, rather than just a 10-year risk, and basing the advice on that figure.

Other free online cardiovascular risk assessment tools:

• ASCVD Risk Estimator
• ASCVD Risk Estimator Plus

If you already know your cholesterol levels, that will make the free online cardiovascular risk assessment tools more accurate. If you have already developed heart disease, then taking statins has been proven to reduce your risk of a heart event, even if your cholesterol levels aren’t high.

Figure 9. Cholesterol levels

Table 1. Normal Cholesterol Levels

Age	Total cholesterol	Non-HDL cholesterol	LDL (“bad” cholesterol)	HDL (“good” cholesterol)
19 and younger	Below 170 milligrams per deciliter of blood (mg/dL)	Below 120 mg/dL	Below 110 mg/dL	Above 45 mg/dL
20 and older Male	125 to 200 milligrams per deciliter of blood (mg/dL)	Below 130 mg/dL	Below 100 mg/dL	40 mg/dL or higher
20 and older Female	125 to 200 milligrams per deciliter of blood (mg/dL)	Below 130 mg/dL	Below 100 mg/dL	50 mg/dL or higher

Footnotes: As you review your results, remember that you want your LDL to be low and your HDL to be high. Ideally, your HDL should be above 60 mg/dL (1.55 mmol/L). It’s the helpful cholesterol. An HDL above 60 mg/dL (greater than 1.55 mmol/L) offers you protection against heart disease.

Table 2. High Cholesterol Levels

Age	Total cholesterol	Non-HDL cholesterol	LDL (“bad” cholesterol)
19 and younger	Borderline high: 170-199 mg/dL High: 200 mg/dL or higher	Borderline high: 120-144 mg/dL High: 145 mg/dL or higher	Borderline high: 110-129 mg/dL High: 130 mg/dL or higher
20 and older	Borderline high: 200-239 mg/dL High: 240 mg/dL or higher	High: 130 mg/dL or higher	Near-optimal: 100-129 mg/dL Borderline high: 130-159 mg/dL High: 160-189 mg/dL Very high: 190 mg/dL or higher

Footnotes: High cholesterol generally means your total cholesterol is 200 mg/dL (greater than 5.18 mmol/L) or higher. But doctors use additional categories like “borderline high” and “near optimal” to break down your results. If your numbers are close to normal levels, they may be easier to manage through lifestyle and dietary changes.

Table 3. Desirable Cholesterol Levels

Desirable Cholesterol Levels
Total cholesterol	Less than 200 milligrams per deciliter of blood (mg/dL) or 5.18 mmol/L
LDL (“bad” cholesterol)	Less than 100 mg/dL (2.59 mmol/L)
HDL (“good” cholesterol)	60 mg/dL (1.55 mmol/L) or higher
Triglycerides	Less than 150 mg/dL (1.70 mmol/L)

[Source ¹²² ]

I have high cholesterol when should I be worried?

There’s no level of cholesterol at which you will or won’t have a heart attack. Most doctors don’t base their advice or treatment on cholesterol results alone unless you have familial hypercholesterolemia. That’s why the numbers above only refer to those at high risk. If you’re not at high risk, your doctor looks at your cholesterol level alongside other risk factors such as blood pressure and body mass index (your weight/height ratio), and lifestyle factors such as smoking, diet and physical activity.

What cholesterol level means I need medication?

A decision about needing medication for high cholesterol is based on all your risk factors, not just the cholesterol. A cardiovascular risk assessment predicts your risk of heart attack or stroke in the next 10 years. A free online computer programme that predicts it is called QRISK, so you may hear your doctor talk about a ‘QRISK score’. If it suggests a 10 per cent risk or higher, you may be offered dietary advice and drug treatment (usually a statin) to help lower your cholesterol. The treatment is usually long-term. Increasingly, we are looking at an individual’s lifetime risk, rather than just a 10-year risk, and basing the advice on that figure.

Other free online cardiovascular risk assessment tools:

• ASCVD Risk Estimator
• ASCVD Risk Estimator Plus

If you already know your cholesterol levels, that will make the free online cardiovascular risk assessment tools more accurate. If you have already developed heart disease, then taking statins has been proven to reduce your risk of a heart event, even if your cholesterol levels aren’t high.

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