Lipoprotein Metabolism

Admin تاريخ التسجيل : 27/03/2008

Introduction

Lipid metabolism disorders, in particular, disturbances of lipoprotein metabolism, (which can be subsumed under the term dyslipoproteinemia) constitute an important risk factor in the pathogenesis of atherosclerosis and/or coronary heart disease (CHD), and other peripheral and cerebral vascular diseases.
Large-scale clinical studies reflect the significance of CHD in today’s society and predict an ongoing dramatic increase in the incidence of CHD and its sequelae for the future. In this context, “essential” phospholipids (PPC), the main active ingredient in PhosChol, are characterized by a unique action profile leading to an amelioration of raised serum lipid parameters in a physiological manner.
Within lipid metabolism, lipoproteins function as an indispensable link between the uptake, storage, and metabolisation/elimination of lipids in the organism. By illustrating this rather complex system of lipoprotein metabolism with its abundance of interdependences we followed up several intentions:

first to bring light into this network of metabolic pathways,
second to elucidate the different sites of action of PPC, and
third to assist in focusing the general practitioner’s interest in the action of PPC in connection with disorders of lipoprotein metabolism.

Please find in the following a brief description of the underlying lipoprotein metabolism followed by remarks clarifying the mode of action of PPC dyslipoproteinemia.

Lipids represent an essential constituent of our daily diet. Among various forms of lipids circulating in the blood stream triglycerides (TG), phospholipids (PL), and cholesterol (Ch) are of particular importance. Briefly, triglycerides form an important energy source for cellular metabolism. Phospholipids are, on account of their amphiphilic behavior excellent emulsifiers of fats and furthermore constitute the predominant element of all biological membranes. Cholesterol has an ambivalent nature: on the one hand it is necessary for the stabilization of biological membrane structure and an essential precursor of hormones and bile acids in hepatic metabolism, on the other hand, a surplus of cholesterol is nowadays generally considered to trigger off a course of pathological events which can be subsumed under the term “atherosclerosis”.

In the interrelation between absorption , transportation, metabolisation, and elimination of lipids, so-called lipoproteins function as transport vehicles for water-unsoluble lipid fractions and lead them to their sites of metabolisation and/or deposition. We can differentiate between four major classes of lipoproteins which can be separated by untracentrifugation on the basis of their density. Additional characteristics are size, composition, and function.
The basic lipoprotein structure comprises a hydrophobic core of triglycerides and cholesterol esters surrounded by a coat containing polar phospholipids, free cholesterol and apoproteins. Apoproteins ensure indentification of receptors for the exchange and deposition of transported lipid fractions.
First of all chylomicrons, containing dietary triglyceride and a small amount of cholesterol, pass into the circulation via lymphatics. Triglyceride is removed in the peripheral circulation by the endothelial enzyme lipoprotein lipase (LPL). The resulting chylomicron remnant, containing most of the origional cholesterol, is taken up by the liver.
Very-low-density lipoproteins (VLDL) are secreted by the liver and contain endogenously synthesized triglycerides and cholesterol a.o. Triglycerides are progressively removed from VLDL by lipoprotein lipase to produce intermediate density lipoproteins (IDL), which can either be reabsorbed by the liver or further dPPCeted of triglycerides to produce low-density lipoproteins (LDL).
LDL, the major carrier of the plasma cholesterol, are taken up by the liver and peripheral cells, largely via receptor recognizing apoproteins B and E. The cytoplasmic pool of cholesterol is derived partly from LDL and partly by endogenous synthesis from acetyl coenzyme A. In the liver, bile salts are synthesized from this pool and, after secretion in the bile, are partly reabsorbed via the terminal ileum and recirculated.
High-Density lipoproteins (HDL) comprise a heterogeneous fraction of particles which carry 20-30% of the total plasma cholesterol. Precursors of HDL (HDL3) are secreted by the liver and accept cholesterol from cell membranes which is esterified by the enzyme lecithin:cholesterol acyltransferase (LCAT).
HDL are involved in reverse cholesterol transport through their ability to accept free cholesterol, esterify it and transfer the cholesterol to other lipoproteins, but mainly and ultimately to the liver for elimination.
With regard to the development of atherosclerosis and its sequelae, LDL are today generally recognized as being highly atherogenic lipoproteins and the main sourse of cholesterol found in the arterial wall. In population studies, the increased risk of atheroma is in correlation with pathological LDL-cholesterol levels, but also inversely correlated with levels of HDL. The protective effect of HDL against atheroma may be due to their ability to transport cholesterol from peripheral cells to the liver.
A comprehensive therapy of hyperlipidemias and atherosclerosis needs to fulfill the following:

to lower raised lipid blood levels (e.g. triglycerides (TG), total cholesterol (T-Ch), LDL cholesterol (LDL-Ch);
to increase the anti-atherogenic fraction of HDL cholesterol (HDL-Ch);
to prevent further deposition of Ch;
to mobilize and remove deposited Ch (in atheromas) from vascular walls, for instance by enhancing the reverse transport of cholesterol to the liver;
to improve flow properties of the blood and its particles;
to reduce raised platelet aggregation. PhosChol (PPC) has shown to influence the a.m. processes positively on various levels:

1- Under healthy conditions lipoproteins are exposed to a permanent attack of lipolytic enzymes, such as lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). In pathological states however, lipolysis can be insufficient.

Administration of PhosChol appears to be able to increase the concentration of these enzymes and by this reduces the amount of serum triglycerides. If the endothelium of the vascular walls is damaged, most of the LDL-Ch accumulates within the cells. Normal enzyme activity is insufficient to metabolize and mobilize the abundant cholesterol. Regarding the reverse transport of cholesterol from the vascular walls to the liver, the enzyme called lecithin: cholesterol acytransferase (LCAT) is of major importance. PPC acts as a substrate for LCAT by delivering preferably linoleic acid and thus increases its activity.

2- In the vicinity of the endothelial surface deposited cholesterol is transformed into linoleic or linolenic esters which are more easily taken up by HDL-particles and consequently stored in the core of these particles than cholesterol esters with saturated fatty acids.

3- PPC do not only activate LCAT on the tissue level but also in serum, resulting in an increased esterification of free cholesterol, which is transferred from other lipoproteins to HDL. Thus cholesterol is removed from atheromas and the cholesterol content of LDL is reduced.

4- PPC is predominantly taken up and incorporated by HDL. By means of this, the surface capacity to take up cholesterol may be significantly increased. This can be deduced from the fact that in “essential” phospholipids unsaturated fatty acids, due to their double-bonds, either take up more space than saturated ones so that the volume of the HDL particles may be increased, or that the increased fluidity accelerates cholesterol incorporation.

5- Incorporation of PPC and activation of LCAT results in an enhanced cholesterol-ester content in HDL, which furthermore leads to an improved LDL/HDL-cholesterol ratio (by ameliorating this particular ratio, PhosChol (PPC) stands out from other preparations).

HDL transport stored cholesterol to the liver, where is is easily metabolized and eliminated with the bile. Apart from that, two further effects of PhosChol (PPC) have to be mentioned

6- By being both lipophilic and hydrophilic, PPC-molecules act as excellent emulsifiers. In the intestine they function as wedges and thus split big fat drops into smaller droplets (micelles). Consequently dietary fats increasingly become targets of intestinal lipases and lipid degradation is favoured from the very beginning.

7- Additionally, PPC are taken up and incorporated into the membranes of platelets and red blood cells and by this obtaining two positive effects:

reducing their tendencies to aggregate and at the same time
raising their membrane flexibility and fluidity.

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