Tuesday , 25 February 2020

Anti-atherogenic effects of HDL

About author :
Amir Khan*,  Anchal Rana
*Dept. of Biotechnology & Biochemistry
Sardar Bhagwan Singh Post Graduate Institute of Biomedical Sciences & Research, Dehradun, India
*e-mail: amiramu@gmail.com

Introduction :
High Density Lipoprotein (HDL) is the most potent lipid predictor of coronary artery disease risk in men and women above 49 years of age. Every 1 mg/dl increment in HDL  is associated with a 2% decreased risk of coronary artery disease in men and a 3% decreased risk in women. Mature HDL presents a hydrophobic core composed of cholesterol esters and triglycerides with proteins embedded in a lipid monolayer composed mainly of phospholipids and free cholesterol. HDL contains several apo lipoproteins, including apo lipoprotein A-1 ( apo A-I) and  apo A-II, the two main proteins and a large number of less abundant proteins including apo C, apo E, apo D, apo J and some enzymes such as LCAT (Lecithin cholesterol acyl transferase), Serum Paraoxonase (PON1) & Platelet activating factor acetyl hydrolase (PAF-AH).
Key words:  LCAT, PON1, HDL, PAF-AH, apo A-I, anti-inflammatory and LDL
Functions  of  HDL :
The inverse relation between HDL cholesterol and risk of cardiovascular disease is well established. The protective effect of HDL has been attributed to its role in Reverse Cholesterol Transport. More recently discovered are the anti-inflammatory and anti-oxidative effects of HDL, which play a key role in preventing atherosclerosis.
Increased LDL oxidation is associated with Coronary Artery Disease. Mild oxidation of LDL in the arterial wall by cell associated Lipoxygenase and/ or Myeloperoxidase causes formation of oxidised LDL which induces atherosclerosis by stimulating monocyte infilteration and smooth muscle cell migration and proliferation. It contributes to atherothrombosis by inducing endothelial cell apoptosis and thus plaque erosion by impairing the anti-coagulant balance in endothelium stimulating tissue factor production by smooth muscle cells and inducing apoptosis in macrophages.
Biological lipids in LDL are formed in a series of three steps. The first step is the seeding of LDL with products of the metabolism of linoleic acid and arachidonic acid as well as with hydroperoxides. The second step is trapping LDL in the sub endothelial space and the accumulation in LDL of additional reactive oxygen species derived from artery cell walls. The third step is the non enzymatic oxidation of LDL phosphoplipids that occurs when a certain certain threshold of reactive oxygen species is reached, resulting in the formation of specific oxidised phospholipids that induce monocyte binding, chemotaxis and differentiation into macrophages.
Normal HDL and its major protein apo A-1 inhibits all three steps in the formation of minimally oxidised LDL. Pre-treatment  of LDL with apo A-1 renders LDL resistant to oxidation and reduces the chemotactic activity of LDL.
“Paraoxonase”, a HDL associated enzyme prevents LDL oxidation by hydrolyzing lipid peroxides, cholesterol linoleate hydroperoxides and hydrogen peroxide. Paraoxonase also renders HDL resistant to to oxidation thereby maintaining tha capacity of HDL to induce reverse cholesterol transport. Another HDL associated enzyme LCAT also prevents accumulation of oxidised lipids in LDL.
The early inflammatory phase of atherosclerosis involves the generation of PAF and oxidised phospholipids with PAF like bio activity in LDL. PAF is a potent lipid mediator, that stimulates macrophages to produce superoxide anions, thus contributing to progression of atherosclerosis. PAF and PAF like oxidised phospholipids are inactivated by HDL associated PAF acetyl hydrolase (PAF-AH), a calcium independent enzyme that hydrolyses the sn-2 group of PAF converting it into lyso PAF
There is no doubt that HDLs have multiple functions beyond their ability to promote the efflux of cholesterol from cells. These non cholesterol transport properties have the clear potential to contribute to the anti-atherogenic effects of HDL, although the magnitude and clinical importance of such effects remain to be determined. It will be important to determine how newer therapies designed to raise HDL cholesterol levels impact on the antioxidant and anti-inflammatory properties of these lipoproteins. It is highly likely that further research directed at understanding these basic processes will yield new strategies for the prevention and treatment of atherosclerosis.

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