LDL

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LDL (low-density lipoprotein) is a group of the lipoprotein family. The other members of the lipoprotein family include HDL, VLDL, IDL, and Chylomicrons. LDL is synthesised in the liver and derived from VLDL and IDL. LDL acts as a transport protein for lipids in plasma and therefore contains a large amount of cholesterol (1500 molecules) and cholesteryl esters[1].

LDL is an acronym for low-density lipoprotein. They are one of five groups of lipoprotein. The main purpose of lipoproteins is to transport lipids around the extracellular fluid of the cells, in this example of low-density lipoproteins, it is to transport cholesterol around the bloodstream. LDL's are often referred to as the 'bad' cholesterol in the blood as they transport cholesterol from the liver into the bloodstream, this can often lead to the formation of plaques in the walls of the arteries, over time this can lead to atherosclerosis.

Contents

Structure

LDLs have a micelle shape; they have a phospholipid monolayer coat with a hydrophobic core inside. The outside coat consists of phospholipids, unesterified cholesterol and an Apoprotein. The hydrophobic core contains the insoluble cholesterol esters and triacylglycerides[2].

The protein part of LDL, called Apoprotein, has a structural and functional role. Structurally, it packages hydrophobic lipids into a soluble form. They can do this because they are amphipathic, so they have hydrophobic regions that interact with lipid molecules and hydrophilic regions that interact with water. Functionally, it is recognised by receptors on cell surfaces so it is very important as it gives lipoproteins their identity. Hence, each type of lipoprotein has its own specific apoproteins; LDL has apolipoprotein B100[3].

It is this difference in the apoproteins, and in the amount of different types of lipid contained, that makes each group of lipoproteins different to each other in terms of size, density and weight.

Function

The main role of LDL is to transport cholesterol, which is synthesised in the liver, to tissues of our body. This is because lipids are insoluble in blood, and cholesterol is a class of lipid known as hydroxy-methyl glutaric acid derivatives. It carries cholesterol as cholesteryl esters[4].

The process of uptake of LDL by cells is known as Receptor-Mediated Endocytosis. Cells have LDL receptors that recognise specific apoproteins and binds to it. The receptor-LDL complex then gets taken into the cell. The ligand, cholesterol, ends up being degraded by enzymes in the lysosome and becomes free cholesterols, whereas the receptor gets recycled[5].

The process of Import:

  1. LDL receptors are expressed on the surface of cell membrane.
  2. Internal signals within cell cause production of clathrin coated pits, which internalize LDL receptors along with any LDL molecules that have bound to them.
  3. Clathrin coated pits shed their coat and deliver their contents to Early Endosome. Low pH in endosomes results in LDL molecules being released from their receptors and passed onto Lysosomes.
  4. LDL receptors are recycled back to cell surface membrane to be reused whilst discharged LDL molecules remain in the lysosome.
  5. Cholestryl Esters in LDL are hydrolysed to free cholesterol molecules which can then be used by the cell in other biochemical reaction, such as the formation of cell membrane for example.

LDL receptor & Receptor Mediated Endocytosis

LDL receptor expression is controlled by cholesterol concentration in the cell; when cholesterol is required by a cell production of transmembrane LDL receptors is stimulated. When there are free cholesterols present in the cell, it prevents further cholesterol and new LDL receptors synthesis[6][7].

The receptors are made in the endoplasmic reticulum and processed in the Golgi body, like most secretory proteins.Internalisation of LDL receptors occurs by a process known as Receptor-Mediated Endocytosis. In this process, there is the spontaneous formation of clathrin-coated pits, which is where LDL binds to its receptor. (Note: clathrin-coated pit formation is spontaneous, so they can form whether the LDL receptors have ligand bound to it or not).

The clathrin-coated pit, along with the LDL and its receptor, is then internalised into a coated vesicle. Inside the cell the vesicle then becomes uncoated and fuses with an endosome, releasing its contents into it. Endosome is where the uncoupling of the receptor and ligand occurs, as it has an acidic environment inside it due to the proton pump located on its membrane. Once the LDL receptor and LDL dissociate from each other, vesicles bud off from the endosome taking LDL to the lysosome. Lysosomes contain the enzyme cholesterol esterase which breaks down the cholesteryl esters. The receptor is recycled[8][9].

Role in disease

LDL that are deposited at the walls of arteries can start to cause big problems, as a rise in LDL levels correlates with an increased risk of Coronary Heart Disease[10]. Hence LDL is also known as the ‘bad cholesterol’, in contrast to HDL which is known as the ‘good cholesterol’.

Hyperlipidaemia is a risk factor for atheroma. When LDLs are deposited at the walls of blood vessels they are oxidized. Macrophages see the oxidized LDLs as being faulty and so engulf them to become foam cells. These foam cells accumulate in the tunica intima (and later on in the tunica media) of the blood vessel wall to form fatty streaks of the plaques of atheroma. If the fibrous cap that contains the fatty core in plaques break off then it can lead to thrombus formation which can then result in an emboli. Atheroma can also lead to thickening and hardening of the arteries, known as Atherosclerosis, which is a common cause of Ischemic Heart Diseases, Stroke and so on[11]. (Note: LDLs are also taken up by smooth muscle cells to become foam cells).

There is also a genetic condition which one can inherit from their parents, called Familial Hypercholesterolemia, which involves high levels of LDL due to deficiency of LDL receptors. Patients with this condition also have high risk of atheromatous disease[12].

Treatment for High LDL levels

Drugs- such as Statins, which reduces plasma cholesterol levels by inhibiting the key enzyme HMG-CoA reductase that is needed for cholesterol synthesis[13]. Diet- low cholesterol diet. Reducing saturated fat in diet also helps, as saturated fat is known to raise plasma cholesterol level[14].

Lifestyle changes- do regular exercise, as exercise can decrease LDL cholesterol levels and increase HDL cholesterol levels, along with other beneficial changes[15][16][17][18][19].

Interpretation of LDL ranges[20]

LDL level Concentraion
Normal Less than 100 mg/dL
Near Normal 100 - 129 mg/dL
Borderline High 130 - 159 mg/dL
High 160 - 189 mg/dL
Very High 190 mg/dL and higher

References

  1. Eugene Braunwald.(2001) (Essential Atlas of Heart Diseases, 2nd Edition, Singapore: Imago Productions (FE) Ltd.
  2. Bruce Alberts, Alexander Johnson, Julian Lewis et al.,(2008) Molecular Biology of The Cell, 5th Edition, USA: Garland Science, Taylor and Francis Group.
  3. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karger
  4. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karger
  5. Bruce Alberts, Alexander Johnson, Julian Lewis et al.,(2008) Molecular Biology of The Cell, 5th Edition, USA: Garland Science, Taylor and Francis Group.
  6. Bruce Alberts, Alexander Johnson, Julian Lewis et al.,(2008) Molecular Biology of The Cell, 5th Edition, USA: Garland Science, Taylor and Francis Group.
  7. Eugene Braunwald.(2001) (Essential Atlas of Heart Diseases, 2nd Edition, Singapore: Imago Productions (FE) Ltd.
  8. Bruce Alberts, Alexander Johnson, Julian Lewis et al.,(2008) Molecular Biology of The Cell, 5th Edition, USA: Garland Science, Taylor and Francis Group.
  9. Eugene Braunwald.(2001) (Essential Atlas of Heart Diseases, 2nd Edition, Singapore: Imago Productions (FE) Ltd.
  10. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karger
  11. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karge
  12. Eugene Braunwald.(2001) (Essential Atlas of Heart Diseases, 2nd Edition, Singapore: Imago Productions (FE) Ltd.
  13. Eugene Braunwald.(2001) (Essential Atlas of Heart Diseases, 2nd Edition, Singapore: Imago Productions (FE) Ltd.
  14. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karge
  15. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karge
  16. Bruce Alberts, Alexander Johnson, Julian Lewis et al.,(2008) Molecular Biology of The Cell, 5th Edition, USA: Garland Science, Taylor and; Francis Group.
  17. Eugene Braunwald.(2001) (Essential Atlas of Heart Diseases, 2nd Edition, Singapore: Imago Productions (FE) Ltd.
  18. Donald F. Weetman, Diana Wood. (1993) Risk Factors for Cardiovascular Disease in Non-Smokers. Switzerland: S.Karger
  19. Medline Plus. Page last updated: 31.10.13. Available at: http://www.nlm.nih.gov/medlineplus/ency/patientinstructions/000386.htm (last accessed 29.11.13)
  20. Medline Plus. Page last updated: 31.10.13. Available at: http://www.nlm.nih.gov/medlineplus/ency/patientinstructions/000386.htm (last accessed 29.11.13)
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