Intermediate-density lipoprotein cholesterol transport

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

Lipoproteins are globular, micelle-like particles consisting of a hydrophobic core of triacylglycerols and cholesterol esters surrounded by an amphipathic coat of protein, phospholipid and cholesterol. The apolipoproteins (apoproteins) on the surface of the lipoproteins help to solubilize the lipids and target the lipoproteins to the correct tissues. There are five different types of lipoprotein, classified according to their functional and physical properties chylomicrons, very low density lipoproteins (VLDLs), intermediate density lipoproteins (IDLs), low density lipoproteins (LDLs), and high density lipoproteins (HDLs). The major function of lipoproteins is to transport triacylglycerols, cholesterol and phospholipids around the body. 

Cholesterol and triacylglycerols are transported in body fluids in the form of lipoprotein particles. Each particle consists of a core of hydrophobic lipids surrounded by a shell of more polar lipids and apoproteins. The protein components of these macromolecular aggregates have two roles they solubilize hydrophobic lipids and contain cell-targeting signals. Lipoprotein particles are classified according to increasing density (Table 26.1) chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Ten principal apoproteins have been isolated and characterized. They are synthesized and secreted by the liver and the intestine. 

Figure 26-21 Reverse cholesterol transport pathway. HDl High-density lipoproteins LDL, low-density lipoproteins tDL, intermediate-density lipoproteins HTL, hepatic lipoprotein lipase LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein apo E, apoiipoprotein E. Cholesterol is removed from macrophages and other arterial wall cells by an HDL-mediated process. The LCAT esterifies the cholesterol content of HDL to prevent it from reentering the ceils. Cholesterol esters are delivered to the liver by one of three pathways ( ) cholesterol esters are transferred from HDL to LDL by CETP and enter the liver through the specific LDL receptor pathway (2) cholesterol esters are selectively taken from HDL by HDL receptors and HDL particles are returned to circulation for further transport or (3) HDL have accumulated apo E and therefore the particles can enter the liver through remnant receptors, (From Gwynne JT. High density lipoprotein cholesterol levels as a marker of reverse cho/estero/ tronsport./ m j Cardiol I989 64 10G-I7G. Copyright 1989, with permission from Excerpta Medico Inc.)...

Hydrolysis of fats in capillaries by lipoprotein lipase yields intermediate-density lipoproteins (IDLs) from VLDLs and chylomicron remnants from chylomicrons (Figure 18.7). IDLs are taken up by the liver and further processed to low-density lipoproteins (LDLs). LDLs are the primary form by which cholesterol is transported to tissues and high-density lipoproteins (HDLs) serve to transport cholesterol from tissues back to the liver. 

ABBREVIATIONS ABCAl, ATP-binding cassette transporter Al apo, apolipoprotein HDL, high-density lipoproteins IDL, intermediate-density lipoproteins kDa, kilodaltons LCAT, lecithin cholesterol acyltransferase LDL, low-density lipoproteins LPL, lipoprotein lipase VLDL, very-low-density lipoproteins. 

LPL converts chylomicrons to chylomicron remnants and VLDL to intermediate density lipoprotein (IDL). These products, which have a relatively low triacylglyc-erol content, are taken up by the liver by the process of endocytosis and degraded by lysosomal action. IDL may also be converted to low density lipoprotein (LDL) by further digestion of triacylglycerol. Endocytosis of LDL occurs in peripheral tissues as well as the liver (Table VI. 1), and is the major means of cholesterol transport and delivery to peripheral tissues. 

Cholesterol is packaged in chylomicrons in the intestine and in very-low-den-sity lipoprotein (VLDL) in the liver. It is transported in the blood in these lipoprotein particles, which also transport triacylglycerols. the triacylglycerols of the blood lipoproteins are digested by lipoprotein lipase, chylomicrons are converted to chylomicron remnants, and VTDT is converted to intermediate-density lipoprotein (IDL) and subsequently to low-density lipoprotein (LDL). These products return to the liver, where they bind to receptors in cell membranes and are taken up by endocytosis and digested by lysosomal enzymes. LDL is also endocy-tosed by nonhepatic (peripheral) tissues. Cholesterol and other products of lysosomal digestion are released into the cellular pools. The liver uses this recycled cholesterol, and the cholesterol that is synthesized from acetyl CoA, to produce VLDL and to synthesize bile salts. 

Chylomicron remnants deliver dietary cholesterol to the liver. It is then incorporated into very low-density lipoproteins (VLDL), which are secreted in plasma. The VLDL acquire cholesteryl esters and apolipoprotein E (apo E) from high-density lipoproteins (HDL) to produce intermediate-density lipoproteins (IDL), which are rapidly taken up by the liver or are further catabolized into low-density lipoproteins (LDL). These cholesterol-rich LDL particles are catabolized only slowly in human plasma and are therefore present at relatively high concentrations. Elimination of cholesterol from these extra-hepatic cells is achieved by the delivery of cholesterol from cell membranes to plasma HDL in the first step of a pathway known as reverse cholesterol transport. This process allows for esterification of cholesterol and its delivery back to the liver. 

Figure 26-6. Transport of cholesterol between the tissues in humans. (C, unesterified choiesterol CE, cho-iesteryi ester TG, triacyigiyceroi VLDL, very iow density iipoprotein iDL, intermediate-density iipoprotein LDL, iow-density iipoprotein HDL, high-density iipoprotein ACAT, acyi-CoA choiesteroi acyitransferase LCAT, iecithinxhoiesteroi acyitransferase A-i, apoiipoprotein A-i CETP, choiesteryi ester transfer protein LPL, lipoprotein iipase HL, hepatic iipase LRP, LDL receptor-reiated protein.)...

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

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