ANTECEDENTES DE LA INVESTIGACIÓN

Each lipoprotein class comprises a family of particles that vary slightly in density, size, migration during electrophoresis, and protein composition. The density of a lipoprotein is determined by the amount of lipid and protein per particle. HDL is the smallest and most dense lipoprotein, whereas chylomicrons and VLDL are the

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largest and least dense lipoprotein particles Most TG is transported in chylomicrons or VLDL, and most cholesterol is carried as cholesteryl esters in LDL and HDL .They function as transport vehicles for lipids in blood plasma &

deliver the lipid components to various tissue for utilization. VLDL transport TG synthesized in the liver mainly to the adipose tissue, whereas the other lipoproteins are especially important in the different stages of phospholipid and cholesterol transport from the liver to the peripheral tissues or from the periphery back to the liver.⁹

Structure^9,10

Lipoprotein consists of a neutral lipid core with TAG or cholesteryl ester, sorrounded by a coat shell of hydrophilic lipids like phospholipids, unesterified cholesterol and apoprotein that interact with body fluids. Polar amphiphilic portion are exposed on surface so that it is soluble in aqueous solution.

Apoprotein is the protein component of lipoprotein which acts as its structural component. It recognizes the cell membrane surface receptors, facilitates transfer of lipids between lipoprotein classes & between lipoprotein & cells. It activates enzymes involved in lipoprotein metabolism.

ApoA-I, which is synthesized in the liver and intestine, is found on virtually all HDL particles. ApoA-II is the second most abundant HDL apolipoprotein and is found on approximately two-thirds of all HDL particles. ApoB is the major structural protein of chylomicrons, VLDL, IDL, and LDL; one molecule of apoB, either apoB-48 (chylomicrons) or apoB-100 (VLDL, IDL, or LDL), is present on each lipoprotein particle. The human liver makes only apoB-100, and the intestine makes apoB-48. ApoE

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present in multiple copies on chylomicrons, VLDL and IDL plays a critical role in the metabolism and clearance of TG rich particles. Three apolipoproteins of the C-series (apoC-I, -II, and -III) also participate in the metabolism of TG rich lipoproteins.

Fig.7: Composition of Lipoprotein ¹⁰

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Metabolism & transport of lipoproteins Transport of dietary lipids (Exogenous pathway) ^9,10

Dietary cholesterol and retinol are esterified by the addition of a FA in the enterocyte to form cholesteryl esters and retinyl esters, respectively. Longer-chain FA are incorporated into TG and packaged with apoB-48, cholesteryl esters, retinyl esters, phospholipids, and cholesterol to form chylomicrons. Nascent chylomicrons are secreted into the intestinal lymph and delivered directly to the systemic circulation, where they are extensively processed by peripheral tissues before reaching the liver. Apoprotein C-II on chylomicron, binds to specific receptors in adipose tissue, skeletal muscle, cardiac muscle and the liver and allows the endothelial enzyme, LPL, to remove most of the TG from the particle and liberating free FA and glycerol. The released free FA are taken up by adjacent myocytes or adipocytes and either oxidized or reesterified and stored as TG.

Some free FA bind with albumin and are transported to other tissues, especially the liver.

ApoC-II, is transferred to circulating chylomicrons or returned to HDL.

The chylomicron particle progressively shrinks in size as the hydrophobic core is hydrolyzed and the hydrophilic lipids (cholesterol and phospholipids) on the particle surface are transferred to HDL. The resultant smaller, more cholesterol ester–rich particles are referred to as chylomicron remnants. The remnant particles are rapidly removed from the circulation by receptors on hepatocytes in a process that requires apo E. Consequently, few, if any, chylomicrons are present in the blood after a 12-h fast, except in individuals with disorders of chylomicron metabolism.

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Cholesteryl esters form an integral part of HDL. From peripheral tissue cholesterol is trapped in HDL by a reaction catalysed by LCAT, transported to liver for degradation and excretion .The process is known as reverse cholesterol transport

Cholesterol ester transfer protein synthesised in liver, facilitates exchange of components between different lipoprotein & thereby transfer cholesterol esters from HDL to VLDL or LDL in exchange for TAG.

Transport of hepatic lipids (Endogenous pathway)⁹,¹⁰

The endogenous pathway of lipoprotein metabolism refers to the hepatic secretion and metabolism of VLDL to IDL and LDL.

The cholesterol in LDL accounts for 70% of the plasma cholesterol in most individuals. Approximately 70% of circulating LDLs are cleared by LDL receptor–

mediated endocytosis in the liver

Long-chain FA are esterified into TAG and incorporated into VLDL, which has aoprotein B-100 as an essential component. Apoproteins C-II and E are incorporated later into VLDL by transfer from HDL particles. As they pass round the circulation, VLDL particles bind through apoprotein C-II allowing TG to be progressively removed by LPL in the capillary endothelium. As VLDL remnants undergo further hydrolysis, they continue to shrink in size, which contain similar amounts of cholesterol and TG leaving a particle, now depleted of TG and apoprotein C-II, called an intermediate-density lipoprotein (IDL) particle which have apoprotein B-100 and apoprotein E molecules on the particle surface. Most IDL particles bind to liver LDL receptors through the apoprotein E molecule and are then catabolized.¹¹

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The liver removes approximately 40 to 60% of VLDL remnants and IDL. The remainder of IDL is remodeled by hepatic lipase to form LDL. During this process, most of the TG in the particle is hydrolyzed and all apolipoproteins except apoB-100 are transferred to other lipoproteins.

LDL particles become Lp(a) lipoproteins as a result of the linkage of apoprotein (a) to aproprotein B-100. Raised levels of Lp(a) lipoprotein is a risk factor for cardiovascular disease. The HDL particle transports cholesterol away from the periphery and may transfer it indirectly to other particles such as VLDL in the circulation or deliver its cholesterol directly to the liver.¹¹

Fig. 8: Transport of Lipids ¹⁰

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HDL metabolism and reverse cholesterol transport ⁹

All nucleated cells synthesize cholesterol but only hepatocytes can efficiently metabolize and excrete cholesterol from the body. The predominant route of cholesterol elimination is by excretion into the bile, either directly or after conversion to bile acids.

Cholesterol in peripheral cells is transported from the plasma membranes of peripheral cells to the liver by an HDL-mediated process termed reverse cholesterol transport. Nascent HDL particles are synthesized by the intestine and the liver. The newly formed discoidal HDL particles contain apoA-I and phospholipids (mainly lecithin) but rapidly acquire unesterified cholesterol and additional phospholipids from peripheral tissues via transport by the membrane protein ATP-binding cassette protein A1 (ABCA1). Once incorporated in the HDL particle, cholesterol is esterified by LCAT a plasma enzyme associated with HDL. As HDL acquires more cholesteryl ester it becomes spherical, and additional apolipoproteins and lipids are transferred to the particles from the surfaces of chylomicrons and VLDL during lipolysis. HDL cholesteryl esters are transferred to apo B containing lipoproteins in exchange for TG by the CETP.

The cholesteryl esters are then removed from the circulation by LDL receptor–mediated endocytosis. HDL cholesterol can also be taken up directly by hepatocytes via the scavenger receptor class BI (SR-BI), a cell-surface receptor that mediates the selective transfer of lipids to cells.

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HYPERLIPIDEMIA

Cardiovascular disease are responsible for 25% & Cerebrovascular disease for 19% of DALY’s lost due to non communicable disease in southeast Asian region countries. More than half the patients with angiographically confirmed premature coronary heart disease have a familial lipoprotein disorder which represents the most common genetic dyslipidaemia with a prevalence of 1 – 2 %. Familial combined hyperlipidemia characterized by elevated levels of cholesterol or TG or both is estimated to cause 10 – 20 % of premature coronary heart disease and 10 % of myocardial infarction.¹²

The abnormal levels of TG and or cholesterol in plasma are consequent to excess of substrate leading to more production, defective transport, delayed peripheral clearance, reduced utilization of Lipoprotein or their intermediaries, or combinations of these abnormalities. The causes responsible for such lipid disorders could be primary, i.e. an inherent genetic (monogenic or polygenic) defect of lipid-Lipoprotein-Apo metabolism or more commonly secondary to certain diseases.¹³

Classification of Hyperlipidemia due to disorders of lipoprotein metabolism ^9,13 1. Primary disorders of Apo B containing lipoprotein catabolism causing elevated

plasma cholesterol levels ( Known etiology)

 Lipoprotein lipase and Apo C - II deficiency / Familial chylomicronemia

 Hepatic lipase deficiency

 Familial dysbetalipoproteinemia

 Familial hypercholesterolemia

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 Familial defective Apo – B 100

 Autosomal recessive hypercholesterolemia

 Wolman disease

 Cholesteryl ester storage disease

 Sitosterolemia

2. Primary disorders of Apo – B containing lipoprotein metabolism ( Unknown