October is Cholesterol Awareness Month – and this is a subject that is rarely out of the headlines. Not everyone agrees on the clinical significance and management of high cholesterol. And of course cholesterol does have important functions in the body – so in this week’s blog we are going to review the topic of cholesterol and outline some natural ways to manage high cholesterol.
The Lipid Hypothesis
The work of Ancel Keys, an American physiologist, led to ‘the lipid hypothesis’ which links raised blood cholesterol levels to the occurrence of heart disease. An accumulation of evidence resulted in the acceptance of the lipid hypothesis by most of the medical community; however, a growing minority argues that the evidence does not support it, and that mechanisms independent of blood cholesterol levels are responsible. This debate is referred to as the “cholesterol controversy”. It is closely related to the saturated fat and cardiovascular disease controversy.
“Most researchers today consider that a high intake of saturated fat and elevated LDL cholesterol are the most important causes of atherosclerosis and coronary heart disease. The lipid hypothesis has dominated cardiovascular research and prevention for almost half a century although the number of contradictory studies may exceed those that are supportive. The harmful influence of a campaign that ignores much of the science extends to medical research, health care, food production and human life. There is an urgent need to draw attention to the most striking contradictions, many of which may be unknown to most doctors and researchers” Ravnskov (2008).
Functions of Cholesterol
Cholesterol is a type of lipid molecule synthesised by all animal cells because it is an essential structural component comprising about 30% of animal cell membranes, where its functions are to maintain membrane structural integrity and fluidity. In addition, cholesterol is a precursor for the synthesis of steroid hormones and bile acids.
Cell membranes: All animal cells are surrounded by a lipid bi-layer that comprises phospholipids (a phosphate group attached to a saturated or unsaturated fatty acid), membrane proteins and cholesterol. Through its interaction with the phospholipid fatty-acid chains, cholesterol alters membrane fluidity and maintains membrane integrity. Within the cell membrane, cholesterol also functions in intracellular transport and cell signalling.
Steroid hormones: Within cells, cholesterol is a precursor molecule for the synthesis of vitamin D and all steroid hormones, including the adrenal gland hormones cortisol and aldosterone, and the sex hormones progesterone, oestrogen and testosterone.
Bile acids: Bile acids are derivatives of cholesterol synthesised by hepatocytes (liver cells) which produce proportionally more cholesterol than other cells (about 20% of the total).
Sources of cholesterol
Since all animal cells manufacture cholesterol, all animal-based foods contain cholesterol in varying amount. Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, fish, and shrimp. Human breast milk also contains significant quantities of cholesterol. However dietary cholesterol intake does not correlate well with blood plasma cholesterol levels. There is a correlation between saturated fat intake and cholesterol levels but most of the circulating plasma level of cholesterol is of endogenous origin (ie produced by the liver).
Synthesis and Transport of Cholesterol
Synthesis of cholesterol within the body starts with the ‘mevalonate pathway’ where two molecules of acetyl CoA condense to form acetoacetyl-CoA. This is followed by a second condensation reaction that is catalysed by the enzyme HMG CoA reductase – this is the rate-limiting step in the synthesis of cholesterol and the primary mechanism of statins is to inhibit this enzyme and thus reduce cholesterol synthesis (coenzyme Q10 synthesis is also inhibited, an unwanted side effect of statins). The HMG CoA reductase enzyme is not the final step in the pathway; over 30 enzyme steps are involved in the synthesis of cholesterol.
The biosynthesis of cholesterol is directly regulated by the cholesterol levels present. A higher intake from food leads to a net decrease in production, whereas a lower intake from food has the opposite effect. A decrease in cholesterol synthesis results in intracellular cholesterol becoming depleted and to compensate for this the number of LDL receptors on the cell surface increase – to allow more cholesterol to enter the cell.
Cholesterol is transported in the plasma within lipoproteins, particles with water soluble proteins on the outer surface and lipid soluble triglycerides and cholesterol on the inner surface. There are several types of lipoproteins in the blood. In order of increasing density, they are; chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
Chylomicrons, which are the least dense cholesterol transport molecules, are assembled in the intestinal cells and carry fats from the intestine to muscle and other tissues in need of fatty acids for energy or fat production. The entire process of chylomicron metabolism is relatively rapid and the presence of chylomicrons in the serum after an overnight fast is considered an indicator of defective lipoprotein metabolism.
Very Low Density Lipoproteins (VLDL) molecules are produced by the liver from triglycerides and cholesterol. VLDL vary in triglyceride content which they exchange with both LDL and HDL for a cholesterol molecule. Triglyceride enriched LDL molecules are then processed through another reaction that removes the triglycerides provided by VLDL. The result is small LDL particles which contribute the most to atherosclerotic disease (ie LDL particles exist as ‘large’ or ‘small’ LDL particles).
Low Density Lipoproteins (LDL) molecules are the major blood cholesterol carriers; they carry cholesterol to cells that need it. Each one contains approximately 1,500 molecules of cholesterol. As explained above LDL molecules are derived mostly from VLDL metabolism and can be described as ‘small’ or ‘large’; it is the ‘small’ LDL that are the most damaging.
LDL molecules provide cholesterol for membrane biosynthesis or storage within the cell. The removal of LDL from the circulation is largely mediated through LDL receptors on the cell surface. The number of LDL receptors on the cell surface is controlled according to the cell’s cholesterol needs. When this process becomes unregulated, LDL molecules without receptors begin to appear in the blood. These LDL molecules are oxidised and taken up by macrophages, which become engorged and form foam cells. These foam cells contribute to atherosclerotic plaque formation which is the main cause of heart attacks, strokes, and other serious medical problems.
In summary, LDL carries cholesterol to the cells that need it, but if there’s too much cholesterol for the cells to use it, it can build up in artery walls contributing to disease of the arteries; for this reason, LDL is known as “bad cholesterol”. However this is an over-simplification as it a sub-type of LDL that is particularly dangerous – referred to as ‘small’ LDL.
High Density Lipoprotein (HDL) particles transport cholesterol back to the liver, either for excretion or for other tissues that synthesise hormones, in a process known as ‘reverse cholesterol transport’. Large numbers of HDL particles correlates with better health outcomes. HDL can remove cholesterol from the macrophages of the arterial wall through a number of mechanisms including an active transport mechanism. Thus increased concentrations of HDL correlate with lower rates of atheroma progression and thus HDL is sometimes referred to as “good cholesterol”.
Lipoprotein (a) (Lp(a)): Lp (a) consists of an LDL like particle. Plasma levels vary widely between individuals and are thought to be mainly due to genetics. Individuals without Lp(a) or with very low Lp(a) levels seem to be healthy – so it is not considered necessary, at least under normal conditions.
Lp(a) is believed to have a role in wound healing and tissue repair; the mechanism may be through its oxidised phospholipids content (OxPL), which are generated by the oxidation of polyunsaturated fatty acid residues and can be formed on cell membranes under oxidative stress conditions, during apoptosis (cell death) or on LDL during its oxidative modification. During oxidative stress there may be uncontrolled generation of OxPL. Pathologically Lp(a) attracts inflammatory cells to vessel walls and leads to smooth muscle cell proliferation. It is thus highly atherogenic and prothrombotic. Lp(a) is considered a causal risk factor for cardiovascular disease (CVD).
Metabolism, recycling and excretion
Cholesterol is oxidised by the liver into a variety of bile acids. These, in turn, are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and non-conjugated bile acids, along with cholesterol itself, is excreted from the liver into the bile. Every day up to 1 g of cholesterol enters the colon. Whilst approximately 95% of the bile acids are reabsorbed from the intestines, between 15 – 75% of cholesterol excreted in the bile is eliminated in the faeces (ie predominantly non conjugated cholesterol). Cholesterol from diet and shedding of intestinal cells is also eliminated in the faeces.
Nutritional and lifestyle approaches to support healthy cholesterol (and triglyceride) levels and metabolism include:
Dietary fibre – fibre can help maintain healthy cholesterol and triglyceride levels through a number of mechanisms:
i) it encourages the growth of friendly gut bacteria that can have beneficial effects on cholesterol levels;
ii) it provides bulk for elimination and so excess cholesterol can be eliminated via the bowel as explained above; constipation will result in lower amounts being excreted and more being reabsorbed into circulation;
iii) it helps with glycaemic control (ie blood sugar regulation) – high blood sugar can increase VLDL/triglyceride production by the liver.
Choose foods such as oats, legumes, apples, carrots and broccoli high in soluble fibre. Oats contain a soluble fibre called beta-glucan 1,3 1,4 which reduces cholesterol – see our previous blog.
Plant sterols – Plants do not contain cholesterol but they contain similar substances called phytosterols which can interfere with intestinal absorption of cholesterol. Some ‘functional foods’ have been developed containing these substances but they may have other undesirable features, so it is best to obtain plant sterols from natural sources such as vegetables, olive oil, nuts (almonds), seeds and legumes.
Healthy fats – monounsaturated fats (found in nuts, seeds and avocado) and omega-3 fats (found in oily fish) have been shown to reduce levels of LDL cholesterol and increase HDL. In addition, omega-3 fatty acids decrease triglyceride concentration by reducing VLDL production. Avoid foods containing trans fats – these are found particularly in processed foods.
Antioxidants – It is oxidised cholesterol that is the most damaging, so a diet high in plant food antioxidants to protect against oxidative stress and cholesterol becoming oxidised is important.
Garlic – garlic has been shown to have cholesterol lowering effects and its antioxidant properties may protect cholesterol from oxidation. One study found this effect enhanced when garlic was taken in conjunction with fresh lemon juice.
Green tea – has been found to contain compounds which have been found to lower cholesterol. It also has antioxidant properties.
Red rice yeast (found in supplements) contains naturally occurring statin-like metabolites. Red rice yeast has been used for centuries as a natural food preservative in China. It has the following permitted health claim “Monocolin K from red rice yeast contributes to the maintenance of normal blood cholesterol levels”. Red rice yeast is not suitable for those taking statins.
High dose niacin has been shown to reduce cholesterol. However it can also raise homocysteine levels (a risk factor for cardiovascular disease) so caution is needed here.
Fermented foods and/or consider a Live bacteria supplement: Lactobacillus plantarum has been shown to have beneficial effects on cholesterol levels.
Carbohydrates stimulate the production of triglycerides which are then transported in VLDL particles. So reducing carbohydrate consumption is an important part of cholesterol management. Choose low glycemic carbohydrates eg sweet potatoes and oats and eat small portions only.
Stress – chronic stress increases demand for steroid hormones and the synthesis of cholesterol by the liver increases to meet demand resulting in raised cholesterol levels in the blood. So stress reduction and management are important to address as well.
If you have any questions regarding the topics that have been raised, or any other health matters please do contact me (Amanda) by phone or email at any time.
email@example.com, 01684 310099
Amanda Williams and the Cytoplan Editorial Team.
Aslani N et al (2016) – Effect of Garlic and Lemon Juice Mixture on Lipid Profile and Some Cardiovascular Risk Factors in People 30-60 Years Old with Moderate Hyperlipidaemia: A Randomized Clinical Trial. Int J Prev Med, 29;7:95
Michael D R et al (2016) – Lactobacillus plantarum can impact cholesterol homeostasis in Caco-2 enterocytes. Benef Microbes, 7, 3, 443-51.
Ravnskov U (2008) – The fallacies of the lipid hypothesis. Scand Cardiovasc J. 42(4):236
Streja D and Streja E (2014) – Management of Dyslipidemia in the Elderly (Book)
Tselepi A D (2017) – Oxidized phospholipids and lipoprotein-associated phospholipase A2 as important determinants of Lp(a) functionality and pathophysiological role. The Journal of Biomedical Research, 2017, 31(00):1-9
Wu A H et al (2012) – Effect of 2 month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women. Cancer Prev Res, 5, 3, 393-402.