Cholesterol

Cholesterol is an essential component found within every cell of the human body, providing structure and stability to the cell membrane, within the mylein sheath it also acts to insulate nerve cells protecting axons. Cholesterol is also essential for the production of other sterols such as cortisol, aldosterone, testosterone, progesterone, estrogens and vitamin D. 70% of cholesterol is produced by the liver with the remaining 30% absorbed from the diet.

Lipoproteins are made from protein, cholesterol, triglycerides and phospholipids. They are known to transport lipids around the body with with the most well known LDL and HDL. This is where the term bad and good cholesterol originates from. LDL is often considered the bad cholesterol as deposits are found in the artery walls, building up to form plaques that may restrict blood flow in the arteries. Further linked with high blood pressure, heart disease and the risk of clots. HDL, considered the good cholesterol may counteract this by preventing plaque from building up by sending it to the liver where it is broken down. 

There a 5 main types of lipoprotein, with them listed from largest to smallest. 

  • Chylomicrons
  • Very Low Density Lipoproteins (VLDL)
  • Intermediate Density Lipoproteins (IDL)
  • Low Density Lipoproteins (LDL)
  • High Density Lipoproteins (HDL)

Structure

Their structure generally consists of a centre of triglycerides, fatty acids, cholesterol esters and fat soluble vitamins, surrounded by an outer hydrophilic layer of apolipoproteins, phospholipids and cholesterol. The size of a lipoprotein can vary from 10 to 1000 nanometres, as the density of the lipoprotein increases the size of the particle decreases.

Chylomicrons, are the least dense of the lipoproteins but have the largest size at around 1000 nm. Their low density is contributed by the high triglyceride content. Chylomicrons are produced in the intestinal mucosa where they transport dietary cholesterol and triglycerides from intestinal cells to the plasma. They work to provide cells with energy-rich triacylglycerol (TAG) which is released through the action of lipoprotein lipase found on the surface of endothelial cells. This enzymes digests the TAG to fatty acids and monoglycerides, which can then diffuse into the cell to be oxidized. For adipose cells however the molecules are taken in and re-synthesized to TAG which is then stored in the cell. Chylomicrons may also acquire apolipoproteins from HDL in the plasma.

VLDL, are around 25-90 nm in size  and like Chylomicrons are a good source of triglycerides for cells within the body. They are composed of around 55-65% triglycerides, and a smaller percentage of cholesterol, phospholipds and proteins. VLDL is considered very bad cholesterol as it may carry triglycerides and lipids to other areas of the body such as the organs, it may also acquire apolipoproteins from HDL in the plasma.

IDL, are derived from VLDL following the depletion of triglyceride stores, this makes them more dense and smaller in size at around 40nm. The quantity of all other components remains the same (proteins, cholesterol esters, cholesterol and phospholipids) as found in VLDL.

LDL, is around 26 nm in size and formed within the liver from the remodelling of IDL, with its role to transport cholesterol to cells in the body. One of its main protein components is Apoprotein B, also found in  chylomicrons, VLDL and IDL, Apo B is thought to act as a ligand, aiding in the recognition and binding of LDL to receptors  on various cell membranes. Once bound the cell may then engulf LDL which can undergo hydrolysis to release cholesterol, needed for the synthesis of hormones or as a structural component. Following this LDL receptors may then be recycled to the cell surface. Each LDL is thought to contain exactly 1 ApoB which makes it a very good marker for detecting circulating LDL levels. Both LDL and HDL transport cholesterol, but LDL makes up more than half of the lipoproteins found within the plasma making it the primary transporter.

HDL, are the smallest in size at around 6-12 nm. They mainly consist of different proteins, including apolipoproteins apo-AI, apo-CI, apo-CII, apo-D, and apo-E. HDL is synthesised and secreted by the liver and small intestine, where it can be seen as a scavenger molecule binding to free cholesterol in the circulation. Following this it will return to liver following various pathways where the choleserol will be broken down into bile acids and secreted by the small intestine. The apolipoproteins aid in this role by binding to different molecules. apo-AI binds to cholesterol molecules in the cell membrane helping with the production of cholesteryl esters. apo-D then activates the transfer of these cholesteryl esters to VLDL and LDL, whilst apo-CII and apo-E are transferred to chylomicrons and other low density lipoproteins. apo-E also recognises and binds to free lipoproteins so that any excess cholesterol may be removed from the circulation and converted to bile acids. In addition to lipid metabolism HDL has roles within the immune response, inflammation, the complement system and as a proteinase inhibitor.


Levels found within the body

A Total Cholesterol of 180 to 200 mg/dL or less  is desired

LDL (Bad) Cholesterol patients with 190 mg/dL or above are considered at high risk. Less than 100 mg/dL is desired.

HDL (Good) Cholesterol HDL cholesterol levels greater than 40 to 60 mg/dL are desired. 

VLDL (Bad) Cholesterol Normal VLDL levels are from 2 to 30 mg/dL.


LDL and its role in heart disease

When lipoprotein particles carrying cholesterol move into the endothelial walls of the arteries they may accumulate and cause damage. Oxidation of LDL by free radicals can also exaggerate this inducing an inflammatory response. From triggering an inflammatory response monocytes migrate into the area and differentiate into macrophages, where they look to ingest the LDL and remove it from the affected area. Following ingestion macrophages turn into foam cells where they are deposited in the endothelium. A plaque develops from smooth muscle cells proliferating to produce a fibrous cap around the foam cells. If the plaque begins to grow it may then reduce the size of the artery, restricting blood flow. If a plaque ruptures this can cause a blood clot to develop and further inhibit the flow of blood in the arteries. This can cause strokes, heart attacks or peripheral thrombosis depending upon the area affected as it becomes starved of oxygen.


Lpa and is role in heart disease

Lpa is a genetic variation of LDL, its exact function is unknown but high levels may increase risk of heart disease. Levels less than 14 mg/dL is desired, whilst above 50 mg/dL is seen as very high risk. Lpa consists of an LDL like particle with an Apo B attached by a disulphide bond to to a specific protein called apolipoprotein(a).

Lpa levels are often thought to be hereditary and strongly influenced by our genetics, particularly the LPA gene which encodes apolipoprotein(a) (Apo(a)).  Variable regions within the LPA gene are understood to cause variations in the size of the protein. With the size of the protein found to be correlated to the plasma concentration of Lpa. (the smaller the size of the protein the more highly concentrated Lpa) The correlation is thought to be caused by the longer processing times to produce larger Apo(a) limiting the concentration found in the plasma. Apo(a) are synthesised within the liver and join to LDL particles on the livers outer surface. With Lpa having a half life of around 3-4 days in circulation.

Unlike HDL and LDL which is influenced heavily by diet, exercise and lifestyle, Lpa is influenced heavily by genetics that means even with good lifestyle choices if Lpa levels are high there is still an increased risk of stroke and heart disease. For this reason Lpa is considered an independent risk factor for heart disease. Due to its small size at high levels Lpa can collect in the arterial walls and penetrate the blood vessel lining leading to endothelial damage. Where it can then induce inflammation and promote the build up of plaques. 

Lpa has also been recognised to share high sequence homology with plasminogen which is involved in the formation of clots. Our bodies have been found to constantly produce and break down blood clots with plasminogens helping to dissolve them by binding to the enzyme plasmin. There is a fine balance between the 2 systems so if Lpa disrupts this by competing with plasminogen the body may begin to favour clots. In addition to this Lpa has only being found in mammals such as humans and monkeys that do not synthesise their own vitamin C. Instead relying on it from their diet. Vitamin C is recognised to have roles within clotting and collagen formation so if levels are low Lpa may take on a surrogate role.

Similar to Apo a Apo B, may also indicate the risk of heart disease as it is a structural component found within many lipoprotein particles. There are two isoforms of ApoB, ApoB 100 and ApoB 48. ApoB 100 is considered the most significant one for heart disease as it is synthesised in the liver whilst ApB 48 is synthesised in the small intestine. In addition ApoB 100 can be found in VLDL, IDL, LDL and Lpa with one ApoB 100 found in each, making it a good marker for measuring lipoprotein concentrations. High levels of Apo B have been associated with plaques and vascular diseases as the lipoprotein particles are able to penetrate the artery wall. Genetic disorders which cause a mutation in the Apo B gene may also be found in patients with Hypercholesterolemia or Hypobetalipoproteinemia.


HDL and lowering the risk of heart disease

As HDL can be seen as a scavenger for cholesterol, removing excess found in the circulation, it may help prevent the build up of plaques. Increasing the levels of HDL within circulation may counteract the negative effects of LDL.  Diet and exercise are one of the main factors that can influence levels, with foods high in monosaturated fats such as nuts, olive oil and fatty fish increasing HDL. Saturated fats and trans fats have been found to increase LDL levels so should be avoided or reduced.  Drugs may also be used to alter levels however in some instances medication has not been found to significantly reduce the risk of heart disease, suggesting several factors are involved in determining a persons risk to heart disease.