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Cholesterol and Statins: Part I

Posted Mar 01 2013 12:00am

Cholesterol & Statins (Part I)
by Yusuf M. Saleeby, MD
to be published in American Fitness magazine (Jan/Feb 2013)

Today when one hears the word “cholesterol” it conjures up thoughts of “something bad”.  Whether we hear about a cholesterol level over 200 from a neighbor, or one of many TV shows preaching the avoidance of cholesterol rich foods, cholesterol always seems to drum up connotations of bad, evil or unhealthy.  This two part series will dispel the myths and urban legends about cholesterol and expand the reader’s knowledge of this rather important steroid compound.  Part II of this series will encompass the atherogenic (plaque forming properties of oxidized native LDL-Cholesterol) and what measures can be taken to minimize the risk of stroke and heart attack specifically focusing on a class of medication call statin drugs.

Although Cholesterol as a solid fatty substance was first isolated a half-century before, recognition was given to the scientist who named it in the early 1800’s.  A French chemist named Michel Eugène Chevreul, while studying bile acids and animal fats, christened this new compound.  He derived the name we use today from two Greek words Chole (of the bile) and stereos (solid) adding the –ol usually used to denote an alcohol component [(3β)-cholest-5-en-3-ol is the chemist’s nomenclature for cholesterol] (Olson, 1998).

Cholesterol is essential to mammalian cells as a major component in cell membranes.  This steroid molecule allows for membrane permeability and the flexibility and fluidity integral to our cells.  Additionally, cholesterol is the substrate or building block of other essential biologic end-products, namely the steroid hormones (testosterone, progesterone, estrogens and DHEA to name a few), the bile acids that help with digestion, and as a precursor substrate to the important vitamin/hormone vitamin D (Hanukogul, 1992). 

Essential to life and proper bodily functions as we know it cholesterol is a double edged sword and has in fact a dark side.  Too much either by dietary intake or endogenous production can cause damage to arteries and lead to cardiovascular disease.  Cardiovascular events such as acute myocardial infarction (heart attack) and cerebral vascular accident (stroke) are the consequence in part to the narrowing of blood carrying vessels to the heart and brain respectively.  This narrowing occurs in great part to the formation of plaques rich in cholesterol that line the lumen of arterial vessels.  After a period of time, growth and maturation these plaques “clog” those vessels.
Breaking down cholesterol into further sub-components sometimes adds to the confusion of the part cholesterol plays in health.  For example there are two major subcomponents of total serum cholesterol called low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C).  One is often referred to as the “bad cholesterol.”  Because LDL-C is responsible for building up on artery walls when there is too much in circulation it is referred to as bad.  Produced in the liver and transported to cells, LDL is rather harmless until levels in the serum get too high or the native-LDL is oxidized by free-radicals and becomes atherosclerogenic (that which forms plaques) (Rosenson, 2010).  On the other hand HDL-C is called the “good cholesterol” in part because the smaller subcomponents are themselves protective and also because it’s main function is to transports cholesterol away from the cells and back to the liver for recycling or disposal.  The higher levels you have of HDL-C in your serum, the lower your chances for cardiovascular disease and its sequelae (Brunzell, 2008; Durrington, 2003).  A caveat recently realized is that lowering LDL-C is not the end-all-be-all of lipid management.  It turns out there are other players in plaque forming dyslipidemia such as triglycerides (TG), apolipoprotein B (apoB), and others that may be as important (or more so) in controlling cardiovascular disease (Miller, 2009; Sierra-Johnson, 2009; Handrean, 2011).  Apolipoproteins are proteins that bind lipids (including cholesterol) making the non-water-soluble lipids easier for transport through the water-based blood and lymphatic systems (Saito, 2004).
The Good, Bad and Ugly of cholesterol. 
Firstly let us discuss the body’s requirements and utilization of cholesterol, that we will call the “good”; then we can discuss how some types of cholesterol can hurt our cardiovascular system, that discussion we will call the “bad.”  And finally, we will reserve the discussion of controlling elevated levels of cholesterol with statin drugs (HMG-coA-reductase inhibitors) and by other means as the “ugly” aspect of our two part series.  Ugly you may ask?  Well there is much controversy and debate on how to lower, what to lower and how far or aggressive we need to get in lowering cholesterol.  There are schools of thought about lowering LDL and others on raising HDL.  Then there are the lipoproteins and triglycerides and their role in this game.
From its formation, cholesterol is made predominately in the liver.  A complex 37-stage enzymatic process has to occur to derive cholesterol from the base substrate substances of acetyl coenzyme A.  An important enzyme called 3-hydroxy-3-methylglutaryl CoA reductase (or HMG-CoA reductase) is critical for the formation of cholesterol in the liver.  This concept is important for our discussion on statin drug therapy.  Statin drugs are effective at lowering cholesterol as they inhibit this crucial enzyme. 
Production of cholesterol is in full force at night while we sleep.  Our bodies produce up to 1000 mg of cholesterol per day on average, while the typical 70 Kg (~150lb) person contains about 35 grams of cholesterol by weight.  Our diet, even the standard American high-fat diet, provides us with only between 200 and 300 mg of cholesterol per day.  So our bodies make more cholesterol than what we can possibly take in orally.  This becomes an important fact in how we can effectively treat elevated cholesterol, and in a way reveals the true etiology of dyslipidemia.  It shows the importance of genetics versus environment.  [Hint:  Dietary restriction of high cholesterol foods is a poor way of controlling dyslipidemia.] can be used in a side bar 
Cholesterol is recycled, first excreted by the liver, making a round trip to our cells and back via LDL-C and HDL-C, and then reabsorbed back into the liver to be excreted as bile acid.  This bile is stored in the gallbladder until needed to help digest ingested foods that contain fats and oils.  Approximately 50% of the excreted bile acids are then reabsorbed in the small intestines and returned into circulation.  These facts are again important when we consider how to manager elevated LDL-C.  The use of drugs that inhibit bile acid reabsorption can in theory work, as can phytosteroils from some plants that mimic bile acids.  Phytosteroils are preferentially secreted back into the gut, thus interfering with normal recirculating of bile acids.
Cholesterol is responsible for the absorption of critically important nutrients via the digestive system as the component of bile acids in bile.  The body’s requirements for vitamins A, D, E and K (all fat soluble) are linked to how well they are absorbed in our intestines when solubilized by bile.  Additionally, fats necessary for good health and energy production also require bile for intestinal absorption.  Cholesterol as a metabolic building block is necessary for the synthesis of vitamin D, and our steroid hormones (sex hormones) as well as those of the adrenal gland such as cortisol and aldosterone (Hanukogul, 1992).
So why all the fear about high levels of cholesterol?
Well it goes back to research showing a strong link between elevated total cholesterol and LDL-C specifically and heart disease.  While not the only major risk factor for coronary artery disease, it remains one of intense focus and scrutiny.  Researchers and drug companies hustled into the arena of determining how to control LDL and how best to drive the numbers down in the masses to relieve our industrialized society of the burden of sudden death by heart attack.  Reduce LDL and total cholesterol and the thinking was increased longevity and a better quality of life.
To put things into perspective if too much LDL is abound and not being utilized by the cells in a productive way, they eventually become oxidized as the lazy loiterers they are and start doing bad things to our artery wall lining.  The process is assisted by macrophages (part of our body’s immune system) which takes up this oxidized-LDL and becomes engorged forming what we refer to as “foam cells”.  These foam cells are trapped in the walls of blood vessels and when they mature over time, become atherosclerotic plaques   They form on arterial walls of our carotid artery, our larger vessels and even the smaller coronary artery vessels. There may be other factors as to why they develop here versus there and it has been theorized that micro-trauma, inflammation or even infectious organisms may play a role.  Non-the-less, as these plaques get larger, they narrow the lumen of the arteries and thus set up a situation for bottlenecking of blood corpuscles passing through.  Add a few clotted platelets and presto, you have a recipe for disaster, a clotted artery unable to provide critical oxygenated blood to distal tissues (myocardium in the case of a heart attack and brain tissue in the case of a thrombotic stroke).  Without the oxygenated blood servicing our cells there is injury and eventual death of those cells which lead to one clutching their chest in pain or loosing neurological function.
To the rescue comes HDL-C, remember this is the good cholesterol.  This high density cholesterol and its lipoproteins are given credit for removing excess cholesterol from peripheral tissues and transporting them back to the liver.  This process known as reverse cholesterol transport is one of the chief functions of this beneficial type of cholesterol thus lowering risk for coronary disease (Gordon, 1989).  So what would do our bodies better, lowering LDL-C or raising HDL-C?  That argument continues.
Why the big focus on total cholesterol and LDL-Cholesterol? 

In 1984 one of the first large scale double-blinded interventional trials called the Coronary Primary Prevention Trial (LRC-CPPT) demonstrated that a decrease in serum cholesterol, by a sequestrant drug called cholestyramine, significantly reduced heart attacks (JAMA, 1984).  From there pharmaceutical companies started their marathon race toward producing some of the most prescribed therapeutics in history that reduces cholesterol.  That will all be discussed in Part II of this series.  Despite the fact that there are other risk factors for heart disease and heart attack/stroke, the focus currently remains fervently on LDL-C and the development of statin drugs for lowering cholesterol. 
Other risk factors may actually be of greater importance to the health of the heart and brain, notably among them are family history/genetics, gender, race, obesity, diabetes, tobacco abuse, hypertension, hypertriglyceridemia, elevated homocysteine, inflammation, chronic kidney disease, sedentary lifestyle, Lp(a), fibrinogen, and elevate Lipoprotein B (Watts, 2011).  Of these it is currently though that the top three risk factors for heart disease and stroke are diabetes mellitus (DM), hypertension (HTN) and tobacco smoking and not LCL-C elevation.  In a 2002 cross-sectional analysis of the Copenhagen City Heart Study lipid disorder as a cardiac risk factor was ranked fifth and sixth overall in importance given one’s gender (Schnohr, 2002).

References:
Olson RE., "Discovery of the lipoproteins, their role in fat transport and their significance as risk factors", J. Nutr. 1998, 128 (2 Suppl): 439S–443S.

Hanukoglu I., "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis.". J Steroid Biochem Mol Biol  1992, 43 (8): 779-804.

Rosenson RS, “Lp-PLA2 and risk of atherosclerotic vascular disease”, Lancet, 2010, Vol. 375, Issue 9725, Pages 1498-1500.
Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum. "Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation". Diabetes Care 2008, 31 (4): 811–22.

Durrington P., "Dyslipidaemia". Lancet 2003, 362 (9385): 717–31.

Miller M, “Dyslipidemia and cardiovascular risk: the importance of early prevention”, QJM (2009) 102 (9): 657-667.

Sierra-Johnson J et. al.,”Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population”, Eur Heart J , 2009, 30 (6): 710-717.

Handrean, S., et. al., “Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients”, Ann Clin Biochem November 2011 vol. 48 no. 6566-6571



Weingärtner O, et. al. (2010). Federici, Massimo. ed. "The relationships of markers of cholesterol homeostasis with carotid intima-media thickness".

Tymoczko, John L.; et, al., (2002). Biochemistry. San Francisco: W.H. Freeman. pp. 726–727.

Gordon DJ, et. al., "High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies". Circulation 1989, 79 (1): 8–15.

Virchow, Rudolf (1856). "Gesammelte Abhandlungen zur wissenschaftlichen Medizin". Germany: Staatsdruckerei Frankfurt. Phlogose und Thrombose im Gefäßsystem. (German)

Steinberg D., “Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I”. J Lipid Res. 2004 Sep;45(9):1583-1593.

Steinberg D.,  "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy". J. Lipid Res. 2006, 47 (7): 1339–51.

Goldstein JL, Brown MS, "Familial Hypercholesterolemia: Identification of a Defect in the Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity Associated with Overproduction of Cholesterol". Proc. Natl. Acad. Sci. USA, 1973, 70 (10): 2804–2808.

The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in Incidence of Coronary Heart Disease. JAMA. 1984;251(3):351-364.

Watts, G., “Republished review: Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient”, Postgrad Med J 2011;87:776-782.

Schnohr, et. al., “Coronary heart disease risk factors ranked by importance for the individual and community: a 21 year follow-up of 12 000 men and women from The Copenhagen City Heart Study”, European Heart Journal (2002) 23, 620–626.


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Yusuf (JP) Saleeby, MD is medical director of WellnessOne and WellnessFirst which offer extensive and advanced cardiovascular and stroke biomarker and genetic analysis, including lipid subtypes, Lp(a), HDL2 and HDL3, LDL1-4, ApoB, NT-proBNP, and  the 4q25, 9p21, ApoE & KIF6 genotypes, and other evaluations.  He is a regular contributor to American Fitness and is on the medical advisory board.  He can be reached for comment at ymsaleeby@gmail.com.
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