Posts Tagged ‘lipoproteins’
How statins work 2: atherosclerosis and LDL cholesterol
Recent studies have revealed that children 8-10 years old are being diagnosed with Type II diabetes, high cholesterol, and high blood pressure at an alarming rate.
Lee Haney
As I said in my previous post, biochemistry is almost infinitely complex, so bear with me as I crawl towards an understanding of the role of statins in reducing LDL cholesterol in the blood stream, thus reducing atherosclerosis, a major feature of heart disease.
Remembering, first, that cholesterol is a sterol, which is a modified steroid with a hydroxyl (alcohol) group coming off carbon 3. It’s a mostly hydrophobic lipid with this tiny polar hydroxyl group added. It’s carried around in the bloodstream by lipoproteins.
I’ll turn now to atherosclerosis – though I don’t currently know whether statins can perform roles other than reducing the build-up of plaque in the arteries.
So, generally, our arteries carry oxygenated blood from the heart to other organs and regions of the body. Atherosclerosis is sometimes called ‘hardening of the arteries’, as sklerosis is from Greek, meaning ‘hardening’, but it’s really a narrowing rather than a hardening, or perhaps it’s better described as both, as we’ll see. Arteriosclerosis is a more general name, while atherosclerosis means blockage or narrowing (stenosis) due to an atheroma, an abnormal accumulation of ‘debris’ or plaque consisting of fat (mostly), calcium and sometimes fibrous tissue in the inner arterial wall (endothelium). These atheroma are difficult to detect before they cause heart attacks or disease, because heart arteries are very small and hidden deep within the chest. They’re also quite mobile and elastic with blood flow. Heart attack and stroke sometimes happen when the atheroma ‘bursts’ – the fibrous cap (of smooth muscles cells, cholesterol-rich foam cells, collagen and elastin) which surrounds the atheroma is ruptured, or breaks free from the arterial wall, causing a blood clot (thrombus). These are sudden events, not easily detected beforehand. Alternatively, major problems arise when the atheroma becomes large enough to defeat arterial flexibility.
There can be symptoms, apart from such major dramas as heart attacks and stroke, which may act as warning signs for atherosclerosis. The narrowing of the arteries means that less blood and oxygen is reaching the cardiovascular system (ischemia), and this may result in vomiting, angina (chest pain), and general feelings of faintness and anxiety. Atherosclerosis of the carotid artery, which feeds the brain, may have different symptoms, including headaches, dyspnea and facial numbness. Atherosclerosis can also affect the function of the liver, kidneys and other organs, and the vascular system.
So what causes atheromas? It seems that these accumulations of plaque are the result of monocyte-macrophage activity. Macrophages are types of white blood cells (leucocytes) that perform immune and cleansing functions. However, we don’t really know why the plaque build-up occurs – though it might be initiated by damage to the endothelium. We do know that atherosclerosis can begin early, and that blood LDL cholesterol is a major factor in the activity that leads to this build-up. That’s why researchers have been rather single-minded about ways of reducing LDL cholesterol, and even on increasing HDL cholesterol levels, though there’s little evidence, apparently, that higher HDL levels are beneficial. Nor, interestingly, is there much evidence that lowering triglycerides has a positive effect on heart disease, while study after study has shown that low LDL cholesterol levels are key to avoiding cardiovascular problems.
Okay, now I’m going to take a few steps back to look more deeply at the role of LDL cholesterol in building atheromas and so causing atherosclerosis. Returning to my vague mention of macrophages and monocytes, here’s a clearer picture, drawn mainly from this excellent video.
- Structure of arterial wall
First, we need to know that the arterial walls are layered. The first layer surrounding the lumen (the tunnel space where the blood flows and where you find red blood cells or RBCs, leukocytes and lipoproteins, etc) is the epithelium, a thin layer of squamous cells. This layer is surrounded by the tunica intima (sometimes the epithelium is described as part of the T intima), an elastic layer quite rich in collagen. It also contains structural cells called fibroblasts, and smooth muscle cells (SMCs). Surrounding the T intima is the tunica media (particularly rich in SMCs), which in turn is surrounded by the thicker, tougher tunica adventitia. In general, the arterial wall becomes stiffer and more fibrous as you move from inner to outer. Atherosclerosis is apparently more of a problem in large and middle-sized arteries which contain more of the protein elastin.
2. Plaque formation
Plaque formation begins, it’s believed, when there’s damage to the thin endothelial layer (only one cell thick) as well as an abundance of circulating low density lipoproteins (LDLs). LDLs (mostly lipid with a small amount of protein) can then move through the damaged layer into the T intima where they become oxidised by ‘reactive oxygen species’ (free radicals) and other enzymes such as metallo-proteases, released by the endothelial cells. These oxidised LDLs, which are now ‘trapped’ in the T intima, will activate endothelial cells to express receptors for white blood cells (leukocytes), particularly the largest types of leucocyte, known as monocytes. So we have this accumulation of oxidised LDLs activating endothelial cells to express adhesion molecules for leucocytes, which brings monocytes and T helper cells into the T intima layer. This movement into tissue transforms monocytes into macrophages (not sure how that happens), and these macrophages then ‘take up’ or engulf the oxidised LDLs and form foam cells. By this time the lipid material dumped into the T intima has created something like a lake of fat, known as a ‘fatty streak’. Foam cells are central to the process of plaque formation and atherosclerosis, as they induce more SMCs into the T intima from the T media by means of a released growth factor, IGF-1 (insulin-like growth factor), and this leads to increased synthesis of collagen in the region, which hardens the plaque build-up, a build-up further fostered by foam cell death which releases more lipid material. Foam cells also release pro-inflammatory cytokines and reactive oxygen species as well as chemokines which attract more macrophages to the site. Upon death they also release DNA material that attracts neutrophils, a very common type of white blood cell. All of this will increase inflammation or plaque build-up in the region.
3. Effects
As mentioned, SMCs contribute to the containment of this inflamed lipid area by releasing proteins such as collagen and elastin, which is used to build a fibrous cap around it. They also stiffen the formation, the atheroma as it’s called, by adding calcium. All of this has the effect of enlarging the atheroma and so reducing the diameter of the arterial lumen in the area, which raises blood pressure as the blood tries to maintain an adequate flow. The calcification of the area also considerably reduces the flexibility of the arterial wall, again resulting in increased blood pressure. Rupture of the fibrous cap may result, which may lead to thrombosis.
So where do statins come in here? Let me quote from an abstract of one academic paper: Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities, published in 2004:
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the first-line choice for lowering total and LDL cholesterol levels and they have been proven to reduce the risk of CHD [chronic heart disease]. Recent data suggest that these compounds, in addition to their lipid-lowering ability, can also reduce the production of reactive oxygen species and increase the resistance of LDL to oxidation. It may be that the ability of statins to limit the oxidation of LDL contributes to their effectiveness at preventing atherosclerotic disease.
Note that oxidation of LDL has the effect of fixing it in the T intima, as mentioned above, so if it’s true, as I presume it is, that statins inhibit LDL oxidation, as well as having other benefits, then they can’t be a bad thing, as long as there aren’t serious side-effects. I’ll continue to explore this topic, as it’s teaching me a lot about the blood, the liver and the circulatory system, inter alia – and it’s great fun. Dr Ben Goldacre has written a book Do statins work? the battle for perfect evidence-based medicine, which hasn’t been released yet, but I intend to get my hands on it and devour it, along with more videos and articles. In the meantime I hope it’s not too controversial to go on saying that the best way to reduce that nasty (but not too nasty) LDL cholesterol is to eat a healthy diet and engage in effective exercise.
PS: haha I know this’ll be unreadable to most, but if anybody finds any egregious error in this, let me know.
References
Atherosclerosis video – Nucleus Medical Media (2009)
Atherosclerosis – pathophysiology, video by Armando Hasudungen (2014)
Atherosclerosis – part 1, Khan Academy video
https://www.ncbi.nlm.nih.gov/pubmed/15177118
https://training.seer.cancer.gov/anatomy/cardiovascular/blood/classification.html
Cholesterol metabolism part 1, video by Ben1994 (2015)
How statins work 1 – stuff about cholesterol, saturated fats and lipoproteins…
filched from Wikipedia – don’y worry, I don’t understand it either – at least not yet
Statins are HMG-CoA reductase inhibitors, according to Wikipedia’s first sentence on the topic. HMG-CoA reductase is an enzyme – a macromolecule that accelerates or catalyses chemical reactions in cells. The enzyme works in the mevalonate pathway, which produces cholesterol and other terpenoids (terpenoids are very common, varied and useful forms of hydrocarbon).
So what does HMG-CoA stand for, and what’s a reductase?
3 hydroxy -3 methyl-glutaryl coenzyme A, which may be explained later. A reductase is an enzyme which catalyses a reduction reaction, and I’m not sure if that refers to redox reactions, in which case reduction involves the gaining of electrons…
But let’s look at cholesterol, which statins are used against. Sterols are lipid molecules with a polar OH component, and ‘chole’, meaning bile, comes from the liver. So cholesterol is a type of lipid molecule produced largely by the liver or hepatic cells of vertebrate animals. Cholesterol is essential for life, and it’s synthesised in the cell via a complex 37-step process (the mevalonate pathway makes up the first 18 of these). It makes up about 30% of our cell membranes, and its continual production is necessary to maintain cell membrane structure and fluidity. In high food-intake countries such as Australia and the US, we ingest about 300mg of cholesterol a day on average. We also have an intake of phytosterols, produced by plants, which might vary from 200-300mgs. Of course, this is massively dependent on individual diets (increased phytosterol intake may reduce LDL cholesterol, but it comes with its own quite serious problems).
The (very basic) structure of cholesterol is shown below.
The body of the molecule (centre) contains 4 rings of carbon and hydrogen – A, B and C are 6-carbon rings, while D has 5. The bonds between rings A and B, and C and D, represent methyl groups. On the left is a hydroxyl group, which is hydrophilic and polar, though the massive body of the molecule is extremely hydrophobic, which is reinforced by the cholesterol tail connected to the D ring. The hydroxyl polarity creates a binding site, which builds structure as the molecule binds to others.
Interestingly, the need for cholesterol synthesis varies with temperature, or climate. This has to do with fluidity and melting points. People who live in colder climates require less cholesterol production because, in cold weather, solid structure remains intact. Hotter climates cause greater fluidity and increased entropy, so more cholesterol needs to be synthesised to create and maintain structure.
So now to the 18-step mevalonate pathway, by which the liver produces lanosterol, the precursor to cholesterol. Well, on second thoughts, maybe not… It’s fiendishly complex and Nobel Prizes have been deservedly won for working it all out and I’m currently thinking that physics is easy-peasy compared to biochemistry (or maybe not). What I’m coming up against is the interconnectivity of everything and the need to be thorough. For example, in order to understand statins we need to understand cholesterol, and in order to understand cholesterol we need to understand lipids, lipoproteins, the liver, the bloodstream, the digestive system… So I sometimes feel overwhelmed but also annoyed at the misinformation everywhere, with chiropractors or ‘MDs’ announcing the ‘truth’ about statins, cholesterol or whatever in 500-word screeds or 5-minute videos.
Anyway, back to work. Cholesterol is a lipid molecule, and lipids are generally hydrophobic (they don’t mix with water, or to be more exact they’re not very soluble in water), but cholesterol has a hydrophilic hydroxyl side to it. Lipids that have this hydrophilic/hydrophobic mix are called amphipathic. Phospholipids in cell membranes are an example. and they interact with cholesterol in the ‘phospholipid bilayer’. As an indication of the complexity involved, here’s a quote from an abstract of a biochemical paper on this very topic:
Mammalian cell membranes are composed of a complex array of glycerophospholipids and sphingolipids that vary in head-group and acyl-chain composition. In a given cell type, membrane phospholipids may amount to more than a thousand molecular species. The complexity of phospholipid and sphingolipid structures is most likely a consequence of their diverse roles in membrane dynamics, protein regulation, signal transduction and secretion. This review is mainly focused on two of the major classes of membrane phospholipids in eukaryotic organisms, sphingomyelins and phosphatidylcholines. These phospholipid classes constitute more than 50% of membrane phospholipids. Cholesterol is most likely to associate with these lipids in the membranes of the cells.
Anyway, perhaps for now at least I won’t explore the essential role of cholesterol in cell structure and function, but the role of ingested cholesterol, the difference between LDL and HDL cholesterol, and how it relates to saturated fats and heart disease, particularly atherosclerosis. As Gregory Roberts explains it in a Cosmos article, saturated fats (found in butter, meat and palm oil) definitely raise total cholesterol…
But what is saturated fat, as opposed to polyunsaturated or mono-unsaturated fat? Most of us have heard of these terms but do we really know what they mean? Here comes Wikipedia to the rescue (because there’s a lot of bullshit out there):.
A saturated fat is a type of fat in which the fatty acid chains have all or predominantly single bonds. A fat is made of two kinds of smaller molecules: glycerol and fatty acids. Fats are made of long chains of carbon (C) atoms. Some carbon atoms are linked by single bonds (-C-C-) and others are linked by double bonds (-C=C-). Double bonds can react with hydrogen to form single bonds. They are called saturated, because the second bond is broken and each half of the bond is attached to (saturated with) a hydrogen atom. Most animal fats are saturated. The fats of plants and fish are generally unsaturated. Saturated fats tend to have higher melting points than their corresponding unsaturated fats, leading to the popular understanding that saturated fats tend to be solids at room temperatures, while unsaturated fats tend to be liquid at room temperature with varying degrees of viscosity (meaning both saturated and unsaturated fats are found to be liquid at body temperature).
Saturated Fat, Wikipedia. I’ve removed links and notes – they’re just too much of a good thing! Apologies for the lengthy quote but I think this is essential reading in this context.
Various fats contain different proportions of saturated and unsaturated fat. Examples of foods containing a high proportion of saturated fat include animal fat products such as cream, cheese, butter, other whole milk dairy products and fatty meats which also contain dietary cholesterol. Certain vegetable products have high saturated fat content, such as coconut oil and palm kernel oil. Many prepared foods are high in saturated fat content, such as pizza, dairy desserts, and sausage.
Guidelines released by many medical organizations, including the World Health Organization, have advocated for reduction in the intake of saturated fat to promote health and reduce the risk from cardiovascular diseases. Many review articles also recommend a diet low in saturated fat and argue it will lower risks of cardiovascular diseases, diabetes, or death. A small number of contemporary reviews have challenged these conclusions, though predominant medical opinion is that saturated fat and cardiovascular disease are closely related.
High density lipoprotein (HDL) cholesterol can be a problem if your levels are low. HDL absorbs cholesterol and carries it back to the liver, from where it’s removed from the body. So generally high levels of HDL will reduce your chances of heart attack and stroke.
As Roberts notes, from the 1950s, heart disease has risen to be a major problem. Heart attack victims have been regularly found to have arteries clogged with ‘waxy plaques filled with cholesterol’. Further proof that cholesterol was to blame came with studies of people with a genetic disease – familial hypercholesterolemia (FH) – which meant that they had some five times the normal levels of blood cholesterol, and suffered heart attacks even as children or teenagers. Also, the rise in blood cholesterol levels and the rise in heart attacks, and heart disease generally, were correlated. This was unlikely to be coincidental.
But what’s a lipoprotein and why the different densities? Here we get into another area of extraordinary complexity. Lipoproteins are vehicles for transporting hydrophobic lipid molecules such as cholesterol, triglycerides and phospholipids through the watery bloodstream or the watery extracellular fluid (blood plasma – the yellowish liquid through which haemoglobin and lipoproteins etc are transported – is a proportion of that fluid). They act as emulsifiers, ‘encapsulating’ the lipids so that they can mix with and move through the fluid. Lipoproteins don’t just come in HD and LD forms – we classify them in terms of their density much as we classify colours in the light (electromagnetic) spectrum. According to that density classification we recognise five major types of lipoprotein in the bloodstream.
Cholesterol arrives in the blood via endogenous (internal) and exogenous (external) pathways. Some 70% of our cholesterol is produced by the liver, so, though diet is an important facet of changing cholesterol levels, finding ways of modifying or blocking liver production was clearly another option. Through studying the way fungi produced chemicals such as penicillin that break down cell walls (a large part of which are cholesterol), Akira Endo was the first to produce a statin from a mould in oranges – mevastatin. That was the beginning of the statin story.
References
https://en.wikipedia.org/wiki/Mevalonate_pathway
https://cosmosmagazine.com/society/will-statin-day-really-keep-doctor-away
Cholesterol metabolism, part one – video by Ben1994 (excellent)
Cholesterol structure, part 1/2, by Catalyst University
https://en.wikipedia.org/wiki/Cholesterol
https://en.wikipedia.org/wiki/Statin