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Cholesterol, an animal sterol, is a waxy substance found in every cell in our body.  Cholesterol is  used  as  a  base for the production of steroid hormones, bile salts, and vitamin D, as well as maintaining cell membrane fluidity. Without cholester- ol we would not be able to properly digest foods, our cell structure would not be able to withstand any changes in temperature, and a significant number of important hormones, such as estrogen and testosterone, could  not be produced. Cholesterol is produced in the liver, from the molecule acetyl-coenzyme-A. A key step in the pathway of cholesterol synthesis is the conversion of HMG-CoA into mavalonate, a process that is controlled by the enzyme HMG- CoA reductase (see Figure 1 of the article ‘Red Yeast Rice with Ankascin-568RTM) This enzyme can block the production of cholesterol making it an important target for cholesterol lowering drugs called statins, but it also controls the production of many other molecules such as co-enzyme-Q10.

That’s why there are so many side-effects of taking these drugs. Nearly 10-12% of patients on statin drugs will experience statin-induced muscle pain. Other potential adverse reactions to statin drugs include elevated liver enzymes, lung disease, and in a small subset of patients can even increase risk for type 2 diabetes mellitus.

The majority of cholesterol is synthesized, recycled, and degraded in the liver. But  how does the cholesterol you eat get to the liver from the gut? And, how is cholesterol transported from the liver to every cell in the body?

Figure 1 (below) shows the processes underpinning the absorption, transportation, utilisation and excretion of fat and cholesterol in  the   body.  First, cholesterol  molecules are transported to the liver via the lymph in complexes called chylomicrons. Chylomicrons are relatively large cholesterol-containing lipid (fat) particles that are processed in the liver, forming ever smaller lipid particles containing a mixture of cholesterol, triglyceride, and protein. These heterogeneous particles are called lipoprotein complexes and are utilized by  the  body  to  ‘chaperone’  cholesterol  to where it is needed.

After dietary fat and cholesterol enters the small intestine chylomicrons formed in the intestine are transported, via lymphatics, to the blood vessels of the circulatory system. An enzyme called lipoprotein lipase, present on blood vessel walls, breaks up (hydrolyses) fats (triacyglycerols) contained in chylomicrons, transferring glycerol and fatty acids to tissues to be used as energy. Chylomicron remnants are taken up and processed by the liver, which synthesises vHDL particles and releases them into circulation. Lipoprotein lipase breaks up (hydrolyses) fats (triacyglycerols) contained in vHDL particles (trans- ferring glycerol and fatty acids to tissues to be used as energy). This process forms LDL particles, which are taken up by tissues through a process called endocytosis. Excess LDL particles are taken up by the liver, which also synthesizes and secretes HDL particles into circulation. Circulating HDL particles scavenge excess cholesterol from blood vessels and tissues return excess cholesterol to the liver. In the liver, excess cholesterol is processed into bile acid, which is excreted (eliminated) from the body.

A person may be at risk of developing ‘fatty streaks’ in blood vessels due to the consumption of a high cholesterol diet, with excess cholesterol in LDL particles being deposited in the lining of large and medium-sized blood vessels. Over time, fatty streaks may lead to the formation of atherosclerotic plaques through pathological inflammatory processes, increasing a person’s risk for cardiovascular events. Increasing a person’s HDL cholesterol levels may actually help to scavenge excess cholesterol from blood vessels/ tissues, and return excess cholesterol to the liver for excretion. Strategies for managing cholesterol focus on reducing total cholesterol and LDL cholesterol, while increasing HDL cholesterol levels.

It is useful to think of lipoprotein complexes as   cholesterol   ‘carriages’   that   transport cholesterol around the body via the blood stream. There are several different types of lipoprotein complex, which are classified based on the ratio of proteins-to-lipid/ cholesterol that they contain. Low-density lipoprotein (LDL) contains a low proportion of protein (or a high proportion of lipid/ cholesterol); the main function of LDL is to transport cholesterol to tissues where it is utilized  for  energy.  In  contrast,  high-density lipoprotein (HDL) contains a high proportion of protein (or a low proportion of cholesterol); its main function is to collect excess cholesterol from tissues and transport it back to the liver for processing and excretion. Chylomicrons, LDL, and a further class of lipoprotein called very low density lipoproteins (vLDL), all have very high fat and cholesterol content as compared with protein-rich HDL.

The net effect of this lipoprotein system is that chylomicrons absorbed from the gut, transport cholesterol to the liver which synthesizes and secretes vLDL and LDL particles. vLDL and LDL particles circulating in the blood are taken up by blood vessels and tissues which use their lipid/cholesterol content as energy. Excess LDL particles in circulation return to the liver where they are taken up by liver cells via LDL receptors. Liver cells also release HDL particles into circulation that scavenge excess cholesterol deposited in blood vessels and tissues. LDL and HDL cholesterol  returning to the liver via circulation can be stored or eliminated from the body (excreted) as bile acid.

Cholesterol and Cardiovascular Health

High levels of cholesterol, triglycerides, LDL, and trans-fats are linked to increased risk of cardiovascular events such as heart attacks and strokes. The build-up (deposition) of cholesterol in blood vessels and tissues can be due to increased cholesterol synthesis, decreased cholesterol utilisation (for energy), or decreased excretion of cholesterol (as bile acid). The nature of the cause of cholesterol build-up, as well as the form of cholesterol in the plasma (i.e. LDL or HDL), is important when determining disease risk and treatment. Genetic disorders can influence the function of the LDL receptor at the surface (plasma membrane) of liver cells. Reduction in uptake of LDL cholesterol into liver cells via the LDL receptor can result in an increased amount of LDL cholesterol in circulation.

Elevated levels of LDL cholesterol in circulation due to genetic effects can lead to an increased risk of adverse cardiovascular events, irrespective of diet and lifestyle in these patients. However, genetic  causes of the increase of cholesterol levels affect only a small proportion of the population diagnosed with high cholesterol; the vast majority of cases of high cholesterol in North America are linked to diet and lifestyle.

Indeed, increased consumption of cholesterol-rich foods can result in increased levels of LDL cholesterol in circulation, which can cause atherosclerosis. Atherosclerosis  is  defined  as  the  loss of arterial elasticity due to blood vessel stiffening and thickening (narrowing). During atherosclerotic plaque formation, excess LDL cholesterol in circulation is deposited as  ‘fatty  streaks’  in  the  innermost  layer  of the lining of large and medium-sized blood vessels. As LDL cholesterol infiltrates into the lining of blood vessels it promotes the production of reactive oxygen species (ROS, highly  reactive  molecules  such  as  OH, H2O2, and O-) that attract immune cells (white blood cells) called macrophages. Although the precise mechanism is not fully understood, macrophages attracted to the site of the fatty streak become ‘foam cells’ which accumulate in the blood vessel lining.

The formation of an atherosclerotic plaque results in the recruitment of more and more immune cells, which initiate an inflammatory process that contributes to the narrowing of the blood vessel. As the plaque continues to grow it may begin to disrupt blood flow and even completely block (occlude) the hollow tube (lumen) of the blood vessel. Narrowing of a blood vessel is called stenosis, and atherosclerotic plaques weaken blood vessels, which can lead to potentially fatal ruptures.

The ‘arthrogenic triad’ is an important set of parameters to be aware of and are known to  increase  a  person’s  risk  for  developing atherosclerosis. The triad includes 1) high blood LDL levels, 2) low blood HDL levels, and 3) high blood triglyceride levels. The risk of atherosclerosis is further increased by the consumption of a low fiber diet – as this reduces the excretion of cholesterol – and an inactive lifestyle – which may increase the likelihood of the LDL cholesterol adhering to blood vessels.

Managing Cholesterol with Bergamot Extract

In order to promote healthy cholesterol levels, it is helpful to think of HDL cholesterol as ‘good’ cholesterol and LDL cholesterol as  ‘bad’  cholesterol.   This   is   because HDL cholesterol  is  able  to  scavenge  excess cholesterol in blood vessels and tissues (transporting it back  to  the  liver  for processing/excretion), while LDL cholesterol deposits cholesterol in blood vessels and tissues (contributing to the build-up of fatty streaks and atherosclerotic plaques). Management of cholesterol levels is therefore aimed at increasing the levels  of HDL cholesterol – with a diet that is rich in ‘good’ fats, i.e. unsaturated, non-trans- fats, such as those found in olive oil or fish oil – and reducing LDL cholesterol (and total cholesterol) – with a diet that is low in ‘bad’ fats, i.e. saturated and trans-fats.

HDL cholesterol may also be improved by eating the citrus fruit Bergamot (often added to Earl Grey tea), which contains relatively high levels of flavonoids (i.e. neoeriocitrin, neohesperidin, and naringin). A study by Toth et al. (2016) found that supplementation with Bergamot extract reduced total cholesterol levels, LDL cholesterol levels, and triglyceride levels, but increased the level of HDL cholesterol in 80 human patients with moderate hypercholesterolemia (high blood cholesterol). Other studies by Glizzoli et al. (2013, 2014) demonstrated similar findings (reduced total cholesterol levels, LDL cholesterol levels, and triglyceride levels, but improved HDL cholesterol levels or LDL/ HDL ratio) in a group of 77 human patients with hypercholesterolemia and 107 human patients with metabolic syndrome (a risk factor for the development of cardiovascular disease). Together, these clinical trials support the use of Bergamont extract as a stand-alone or complimentary therapy (to be taken in conjunction with cholesterol- lowering statin drugs) that contributes to cardiovascular health.

In summary, understanding how cholesterol is processed in the body is key to managing healthy cholesterol levels. Natural supplements, such as Bergamot extract, may contribute to reducing total cholesterol and LDL cholesterol, while increasing HDL cholesterol levels and therefore may be useful additions in the management of healthy cholesterol levels.

Key Terms

Total cholesterol The total amount of cholesterol present in a sample of blood (or pasma), regardless of whether a component of chylomicron, vLDL, LDL, or HDL particles. The reduction of total cholesterol, through modification of diet (i.e. low cholesterol diet) is a key strategy for the management of healthy cholesterol levels.

LDL cholesterol Low-density lipoprotein (LDL) cholesterol refers to lipoprotein particles synthesised and secreted into circulation by the liver. This type of lipoprotein particle is low-density because it contains a low ratio of protein-to-lipid.

LDL particles are also called ‘bad’ cholesterol because they are relatively rich in cholesterol, and deposit excess cholesterol in blood vessels and tissues. Reduction of LDL cholesterol is a key strategy for the management of healthy cholesterol levels.

HDL cholesterol

High-density lipoprotein (HDL) has a high protein-to-lipid ratio and is relatively poor in cholesterol. HDL particles actually scavenge excess cholesterol from blood vessels/ tissues. Increasing HDL cholesterol is a key strategy in managing healthy cholesterol levels.

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