Understanding the Cholesterol Skeptic

A Crash Course in Understanding Lipoprotein Metabolism:

Lipoproteins are transporter molecules for cholesterol, fat and other fat soluble nutrients like vitamins A, K, D and E from the blood to different organs (liver) and tissues (adipose and other cells).  Cholesterol like all the other fats and fat-soluble vitamins are not water-soluble and do not dissolve in the blood, hence the requirement to be carried in “packages” called lipoproteins.  Lipoproteins consist of the following parts:

  • A core of fats (triglycerides), cholesterol esters (cholesterol linked to fatty acids), and fat-soluble vitamins.
  • A monolayer membrane of phospholipids and small amounts of free cholesterol.
  • Proteins called “apoprotein” which may be “integral” apoproteins (apoA or apoB) penetrating as a transmembrane protein through the monolayer membrane, compared to the “peripheral” apoproteins (apoC or apoE) that are on the outer surface of the phospholipid membrane.

Apoproteins are named according to their protein density for example “high density lipoprotein” (HDL) has high density protein and “low density lipoprotein” (LDL) contains low density protein.  There are 5 distinct lipoproteins:

  • Chylomicrons
  • VLDL (very low density lipoproteins)
  • IDL (intermediate density lipoproteins)
  • LDL (low density lipoproteins)
  • HDL (high density lipoproteins)

Each lipoprotein contains a specific content of protein, triglyceride, cholesterol and cholesterol ester (see table).

 

Chylomicron

VLDL

IDL

LDL

HDL

Protein

1%

10%

10%

20%

50%

Triglyceride

88%

56%

29%

13%

13%

Cholesterol

1%

8%

9%

10%

6%

Cholesterol ester

3%

15%

39%

48%

30%

As you can see from the table the large chylomicron molecules and VLDL are the main carriers of triglyceride in our blood compared to the IDL, LDL and HDL molecules carrying predominantly cholesterol ester.  Remember from my previous blog on “fats” that triglyceride molecules consist of one glycerol molecule attached by an ester bond to 3 fatty acid molecules.  Triglycerides form the basis of our energy stores of fatty acids and may provide fuel for beta-oxidation to generate ATP (energy).

Cholesterol esters are simply cholesterol esterified to one fatty acid molecule and is essentially the mechanism by which cholesterol is transported around the body to various cells for the important use in cell membranes (with poly unsaturated fatty acids and saturated fatty acids).  The integrity and stability of cell membranes is entirely dependent on the relative content of these fatty acids and cholesterol.  Cholesterol is also the precursor of many very important hormones including Cortisol, Aldosterone, Testosterone and Estrogen, all vital to optimal health.

Chylomicron metabolism:

Chylomicrons are the lipoprotein packages transporting fat from our diet to adipose tissue in our body and the liver.  Our intestines package cholesterol, fats, and fat-soluble nutrients and vitamins into chylomicrons in the enterocyte cell lining the small intestine. The apoprotein that these lipoproteins get is apoB-48. It is an “integral” apoprotein (transmembrane protein) and is a shortened form of apoB-100, being approximately 48 percent as long.

The chylomicron is a very large molecule with the typical phospholipid and cholesterol monolayer with aopB48 and in the core of the chylomicron mostly triglycerides (see table above). 

Chylomicrons enter the lymphatic circulation and make their way via the thoracic lymph duct to the circulation where the duct empties into the subclavian vein in the neck. 

In the blood stream the chylomicrons acquire two new apoproteins, both peripheral apoproteins; apoC and apoE.  The chylomicrons travel either to the liver or adipose tissue.  In the liver the hepatocytes binds the apoE on chylomicrons via the LDL receptor (LDL-R) on the surface of the hepatocytes and the chylomicron is taken into the liver cell where the triglycerides will be used in metabolism.  The chylomicron will also bind preferentially to adipocytes via the apoC lipoprotein to lipoprotein lipase (LPL) an enzyme on the surface of the adipocyte.  The LPL cleaves the triglycerides in the chylomicron and the glycerol and free fatty acids enter the adipocyte thus depleting the chylomicron of triglyceride content and filling the fat cell with fatty acids.  When triglyceride is reduced to ~ 20% in the chylomicron the apoC dissociates from the chylomicron and this reduced triglyceride lipoprotein with only apoB48 and apoE is now called a “chylomicron remnant”. 

The chylomicron remnant is cleared from the circulation by the liver cell (hepatocytes) via the chylomicron remnant receptor on the hepatocytes, binding to the apoE on the remnant particle.  The liver then makes use of the remaining triglyceride.

VLDL, IDL and LDL metabolism:

VLDL lipoproteins are made by the liver for the purpose of transporting fat from the liver to other tissue especially adipose tissue. VLDL carries mainly triglyceride and cholesterol ester (see table above) and the each VLDL containing one apoB100 integral apoprotein in the monolayer membrane.

The VLDL passes into the blood stream and like chylomicron acquires two further apoC and apoE surface apoproteins actually obtained from HDL molecules.  Again identical to chylomicrons the VLDL binds the adipocyte via the apoC to LPL on the adipocyte with the enzyme cleaving the triglyceride to glycerol and fatty acids to be used by the adipocyte. 

As the triglyceride in the VLDL drops to 50% the VLDL dissociates from the LPL and returns to the liver binding to the LDL-receptor (LDL-R) via the apoE on the VLDL.  If the VLDL attached to the adipocyte stays attached longer or attaches to another adipocyte and depletes the triglyceride to 30% the lipoprotein becomes an IDL molecule which is triglyceride depleted and thus has more percent cholesterol ester.  The IDL is taken up by the liver by the LDL-R via apoE.  IDL can also rebind to adipocytes to deplete itself more of its triglyceride to ~ 10% where the IDL loses the apoE and apoC peripheral apoproteins and becomes a cholesterol ester rich LDL molecule with only one apoB100 apoprotein per LDL molecule.  So LDL looks similar to VLDL with a single apoB100 apoprotein but unlike the VLDL that is triglyceride rich the LDL is cholesterol ester rich and is the MAIN carrier lipoprotein to transport cholesterol via its ester to the liver and other cells throughout the body. 

Importantly the LDL molecule does not have apoE or apoC and is therefore not cleared from the blood by the liver as the LDL-R has high affinity for the apoE.  The apoB100 in LDL has a much lower affinity for the LDL-R on the hepatocytes and as a result the ½ life of LDL in the blood is much longer than all the other lipoproteins like VLDL; IDL both of which have apoE to bind the LDL-R on the liver cell.

The consequence of the long ½ life of LDL in the plasma is the LDL is susceptible to oxidative modification of the phospholipid monolayer containing polyunsaturated fatty acids. 

This is where the MISNOMER arises with LDL labelled as the “BAD” cholesterol. LDL is just the main carrier of cholesterol required by all cells in the body.  It is NOT the cholesterol that is atherogenic (causing atherosclerosis), it is the damaged oxidized LDL lipoprotein that is taken up by macrophages in the sub endothelial space of the arterial lining. 

The problem is that LDL is our carrier of cholesterol and so high LDL particularly when oxidized is directly associated with high risk for vascular disease.

A word on HDL metabolism:

HDL is the lipoprotein transporting cholesterol from the tissues back to the liver for excretion into bile for elimination in the bowel but in the small bowel 70% of cholesterol excreted ultimately is reincorporated with diet fat into chylomicrons in the enterocyte to begin the whole process again. 

HDL is synthesized by the liver cells (and other gastro intestinal cells) and is a unique lipoprotein containing one integral transmembrane apoA apoprotein.  HDL when synthesized has very little triglyceride or free cholesterol and is essentially “empty” as its job is to acquire cholesterol from the periphery to transport back to the liver.  In the circulation the empty HDL acquires an enzyme LCAT (lecithin-cholesterol-acyltransferase).  The HDL with LCAT imbedded in its monolayer membrane attaches to any cell binding to the cholesterol esters in the outer layer of the phospholipid bilayer cell membranes and the LCAT attaches to the Hydroxy group on the cholesterol ester and extracts the ester from the outer cell membrane into the HDL molecule.  Thus HDL takes cholesterol from peripheral cells and loads the cholesterol ester into the HDL and transports this back to the liver attaching to the apoA-receptor on the liver cell for the cholesterol to be synthesized in bile.

So in deficient HDL (low HDL) states there is less of this carrier molecule to unload the cells and arterial wall of cholesterol content hence an independent risk for vascular disease.  Like LDL you can equally understand the MISNOMER of HDL being “good cholesterol” as low levels potentiate vascular disease whilst high HDL tends to protect against atherosclerosis BUT it is NOT cholesterol that is implicated; it is the carrier molecule HDL. 

Cholesterol is cholesterol and is a fat for cell membrane integrity, stability and synthesis of steroid hormones.  However with cholesterol’s association with the carrier molecules it is NECESSARILY implicated in vascular disease.  Just as smoke is a marker of a fire; smoke is not the cause of fire but the presence of lots of smoke necessarily suggests a nasty fire?

So now you understand the whole lipoprotein story………..

How do LDL and HDL Affect Atherosclerosis?

To clarify:

LDL (the main cholesterol rich) lipoprotein and if it spends too long in the circulation by poor hepatic uptake tends to oxidize. The polyunsaturated fatty acids (PUFA) in its membrane get damaged by free radicals, and then they proceed to damage the protein in the surface, and finally the fatty acids in the core.

Once LDL oxidizes, it can invade the arterial wall in areas that experience disturbed blood flow (turbulence), like the points where arteries curve or branch. These areas are permeable to large molecules. Oxidized LDL attracts immunocompetent white blood cells (to repair the artery) and initiate an inflammatory cascade that produces the unstable arterial plaque.  This is the basis of the “oxidized LDL theory of atherosclerosis”.

Much has been made of the “reverse cholesterol transport” mechanism whereby HDL extracts cholesterol from arterial plaques, but HDL has other importance roles in atherosclerosis with its antioxidant and anti-inflammatory properties key to the protective effect of HDL.

What is Lipoprotein “a” or Lp(a)?

Lipoprotein “a”, often abbreviated Lp(a), is essentially a subset of LDL. Lp(a) is a strong and independent risk factor for atherosclerosis and is found in arterial plaque. One hypothesis put forward in the late 1980s suggested that Lp(a) promotes blood clotting by inhibiting an enzyme that breaks down clotting factors.

More recent research has shown that virtually all the LDL containing oxidized phospholipids in the blood is associated with Lp(a). Moreover, oxidized LDL transfers oxidized phospholipids from its membrane directly to the Lp(a) particle. Thus, Lp(a) appears to be a marker for oxidation of the LDL membrane, although it is possible that Lp(a) also picks up oxidized phospholipids from the membranes of cells, such as the endothelial cells that line the blood vessel wall.

The Importance of the LDL Receptor (LDL-R) to Vascular Disease

We have seen from my previous dialogue the longer LDL remains in the circulation and not cleared by the LDL receptor the more chance the LDL has of undergoing oxidative modification to become atherogenic.  So clearly there would be MULTIPLE mechanisms of increased risk for atherosclerosis:

  • Having too much LDL in your blood stream by simply “overloading” the delicate lipoprotein cycle.  We see this practically in obesity and metabolic syndrome where a constant release of fatty acids in the circulation from adipose tissue is expressed by high plasma triglyceride content; increased LDL; increased VLDL and IDL and low HDL.  
  • Having high oxidative stress within the circulation seen in smokers; obesity and metabolic syndrome; lack of physical exercise and cardiovascular conditioning; diets high in TRANS-fats and oxidized polyunsaturated omega-6 fats; diets low in omega-3 fats and natural whole food antioxidants; hypertension and diabetes.
  • Having too little LDL-R number or activity (familial hypercholesterolaemia and PCKS9 gene alterations).  If LDL receptors are missing/defective as in familial hypercholesterolaemia or down regulated by the action of the PCKS9 gene the LDL is not cleared from the circulation allowing more time for the LDL to undergo oxidative modification and damage to the arterial wall.  Defective apoB100 lipoproteins on LDL can cause poor LDL-R uptake even if the LDL-R is normal.  On the other hand, people with genetic defects in the PCSK9 gene leading to up-regulation of the LDL-R have a greatly reduced risk of heart disease. Two percent of African-Americans have a mutation that deletes the PCSK9 gene product, an enzyme that would under normal circumstance degrade the LDL-R.  Those individuals possessing this mutation have an 88 percent reduced risk of heart disease. This constitutes an almost complete abolition of heart disease over their lifetime.
  • LDL production is influenced by other hormone systems, and contributes to elevation and oxidative damage to the LDL. Low levels of Thyroid hormone (hypothyroidism); high estrogen levels (obesity/ metabolic syndrome) and elevated glucocorticoid hormone (people taking Prednisone) is associated with high LDL.

So to Summarize:

  1. You can see why TOTAL cholesterol in the blood measured during a lipogram is a poor predictor for heart disease.
  2. You now understand that LDL is the molecule that is pivotal to the initiation of atherosclerosis and that the attempt to heal the damage to the artery mediated through the immune system actually causes an inflammatory cascade potentiating the development and instability of the plaque.
  3. As LDL is the MAJOR carrier of our cholesterol, a measure of high LDL as LDL-cholesterol, is a very powerful determinant of vascular disease.
  4. This is compounded by the clinical states with low HDL syndromes.
  5. Elevated blood triglyceride is usually accompanied by high levels of VLDL and IDL although these are not measured in a lipogram.  You will see that in the setting of high triglyceride the HDL is often low and so if you subtract the HDL from the total cholesterol you are left with the “non-HDL” fraction.  The represents ALL the atherogenic lipoproteins (LDL + IDL + VLDL) and is an excellent predictor for vascular disease.
  6. As more and more oxidation of LDL occurs and the LDL molecule becomes smaller and dense (so-called B-pattern of LDL) compared to the A-pattern of LDL (buoyant unoxidized fluffy large LDL).  Pattern A is minimally atherogenic compared to the highly atherogenic B-pattern. 
  7. A particularly GOOD way of assessing your “total” atherogenic risk is to ask the lab for an apoB level as this reflects your total atherogenic burden from all the apoB containing lipoproteins (LDL + VLDL + IDL).
  8. Statins work by switching off the rate-limiting step of cholesterol synthesis in hepatocytes thus decreasing the amount of cholesterol in the liver cell.  The cell is led to believe it is deficient in cholesterol and therefore up-regulates the LDL-R on the surface of the cell to remove more LDL from the circulation to boost the intracellular cholesterol.  Circulating LDL is removed thus shortening the plasma ½ life making oxidative damage less.
  9. PCSK9 inhibitors also increase the expression of LDL-R allowing better plasma clearance of LDL accounting for lower plasma LDL and thus less cardiac risk.
  10. Ezetimibe works by blocking the absorption of cholesterol uptake at the brush border of the enterocyte and thus reduces the total available cholesterol and cholesterol ester to be incorporated into chylomicrons which ultimately lead to less LDL via a knock-on effect.

So I guess the cholesterol skeptic has good foundation for their belief but they are misguided to suggest the “lipid theory of atherosclerosis” is nonsense. 

Way back in 1913 Nikolai N. Anichkov (1885-1964) demonstrated the role of cholesterol in the development of atherosclerosis. His classic rabbit experiments paved the way to our current understanding of the lipid theory of atherosclerosis with Anichkov’s research often cited amongst the greatest discoveries of the 20th century.

Perhaps the most striking finding reflecting back on Anichkov’s work was that if you fed rabbits a diet high in cholesterol the rabbits promptly developed atherosclerosis.  Anichkov injected intravenously, rabbits with cholesterol only to find no atherosclerosis indicating the role of what we know today with the role of lipoproteins packaging and carrying cholesterol.  A later group of scientists (Gofman’s group) confirmed that Anichkov was correct but they did something that Anichkov could not have done in 1913-they developed and used an ultracentrifuge capable of rotating its tubes 40,000 times per minute. The hypercholesterolaemic serum samples of their cholesterol-fed rabbits were centrifuged and then sequestered into 2 distinct compartments. The 1st fraction was designated low-density lipoprotein (LDL) cholesterol, because it floated toward the surface of the serum sample. The 2nd fraction was deposited at the bottom and was designated high-density lipoprotein (HDL) cholesterol. Gofman’s group showed that injecting that low-density lipoproteins cholesterol into rabbits and a host of other animals caused rapid development and progression of atherosclerosis.

What are the Practical Implications for You?

  1. Undergo cardiovascular risk stratification annually to assess your global risk for vascular disease.
  2. Document your LDL; HDL and calculate your non-HDL as a baseline and see whether you are Lipoprotein “a” positive or negative.  If  you are Lp “a” + you need to be even more aggressive with LDL reduction and HDL elevation (to specified goal targets).
  3. Document your “ultrasensitive C-reactive protein (us-CRP) as a marker of your systemic (vascular inflammation) for if  > 1.0 mg/L then you need therapy to lower us-CRP to < 1.0 and to keep LDL < 1.8-2.5 and HDL > 1.2.
  4. Document your total “apoB” as a measure of your “total atherogenic lipoproteins” for if your LDL is low but apoB high then you likely have small dense atherogenic LDL and perhaps high IDL and VLDL as direct risk for atherosclerosis.
  5. Finally document you Omega-3 Index to ensure optimal (omega-3) fatty acid composition in your (red cell) membranes for cellular stability.

 

Proverbs 4:23

Above all else, guard your heart, for everything you do flows from it.

Blessings

Cardiologydoc

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7 thoughts on “Understanding the Cholesterol Skeptic

  1. Super article. Thanks
    How much better would the health of our country be if the medical myth surrounding cholesterol were replaced with this science.

  2. Pingback: Biology: Treatments of CVD | Revision Systems, Inc. - AS Level.Revision Systems, Inc. – AS Level.

  3. Pingback: My Blog » The Straight Dope on Cholesterol – Part IX

  4. Great Article, thank you. What happens to the extra LDL accumulated by the liver as a result of statins? Can it harm the liver?

    • Hi Stephen

      The statin group of drugs switch off the rate limiting step of Cholesterol synthesis (HMG Co Reductase) in the liver. This reduces intracellular cholesterol so the liver up regulates the LDL receptor to increase clearance of LDL from the circulation. The LDL in the liver is then metabolised to release the cholesterol. There is NO evidence for chronic liver disease with statin use.

      Regards
      Cardiologydoc

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