Cholesterol intermediate-density lipoprotein

Rabbits fed 30 mg/day acarbose showed reduced levels of plasma cholesterol, intermediate-density lipoprotein (IDL) and LDL (Kritchevsky et al., 1990) sudanophilia was reduced by 23% in rabbits fed 7.5 mg/day acarbose and by 43% in rabbits fed 15 or 30 mg/day (Kritchevsky et al., 1990). The decrease in total cholesterol was shown to be a consequence of a significant reduction in LDL cholesterol. Since HDL cholesterol concentrations remained unal-... 

Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of chylomicrons and in the loss of apo C (which remrns to HDL) but not apo E, which is retained. The resulting chy-lotnicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol (Figure 25-3). Similar changes occur to VLDL, with the formation of VLDL remnants or IDL (intermediate-density lipoprotein) (Figure 25-4). 

Figure 25-4. Metabolic fate of very low density lipoproteins (VLDL) and production of low-density lipoproteins (LDL). (A, apolipoprotein A B-100, apolipoprotein B-100 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylglycerol IDL, intermediate-density lipoprotein C, cholesterol and cholesteryl ester P, phospholipid.) Only the predominant lipids are shown. It is possible that some IDL is also metabolized via the LRP.

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

Choi, cholesterol TG, triglyceride CHD, coronary heart disease LDL, low density lipoproteins LPL, lipoprotein lipase VLDL, very low density lipoprotein HDL, high-density lipoprotein IDL, intermediate-density lipoprotein. 

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...

The loss of triacylglycerol converts some VLDL to VLDL remnants (also called intermediate density lipoprotein, IDL) further removal of triacylglycerol from VLDL produces low-density lipoprotein (LDL) (Table 21-2). Very rich in cholesterol and cholesteryl esters and containing apoB-100 as their major apoli-poprotein, LDLs carry cholesterol to extrahepatic tissues that have specific plasma membrane receptors that recognize apoB-100. These receptors mediate the uptake of cholesterol and cholesteryl esters in a process described below. 

LDL = low-density-lipoprotein IDL = intermediate-density lipoprotein C = cholesterol CE = cholesterol esters. Apo B-100, apo C-ll, and apo E are apolipoproteins found as specific components of plasma lipoproteins. Lipoproteins are not drawn to scale (see Figure 18.13 for details of the size and density of lipoproteins). 

Figure 21-1 Movement of triacylglycerols from liver and intestine to body cells and lipid carriers of blood. VLDL very low density lipoprotein which contains triacylglycerols, phospholipids, cholesterol, and apolipoproteins B, and C. IDL intermediate density lipoproteins found in human plasma. LDL low density lipoproteins which have lost most of their triacylglycerols. ApoB-100, etc., are apolipoproteins listed in Table 21-2. LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein (see Chapter 22).

Lipoproteins are particles with hydrophobic core regions containing cholesteryl esters and triglycerides. Unesterified cholesterol, phospholipids, and apoproteins surround the core. Certain lipoproteins contain very high-molecular-weight B proteins that exist in two forms B48, which is formed in the intestine and found in chylomicrons and their remnants and B100, synthesized in liver and found in VLDL, VLDL remnants (intermediate-density lipoproteins IDL), LDL (formed from VLDL), and the Lp(a) lipoproteins. 

Hyperlipidemia (mainly hypercholesterolemia) is a regular part of nephrotic syndrome (K13, W6). Serum levels of cholesterol are often markedly elevated, usually above 10 mmol/L. However, in severely malnourished patients, normal or even decreased serum cholesterol level can be found. Serum levels of triacylglyc-erols fluctuate, from normal values to markedly elevated values (mainly in patients with proteinuria higher than 10 g/24 hr). There is a variable increase in plasma concentrations of very low density lipoproteins (VLDL, they correlate negatively with serum albumin level), intermediate-density lipoproteins (IDL), andLDL however, plasma concentrations of HDL are usually normal (J3). Levels of lipoprotein(a) [Lp(a)j are also increased (W4). Remission of nephrotic syndrome or decrease of proteinuria may result in the decrease of plasma concentrations of Lp(a) (G2). Concentration of free fatty acids in serum is commonly decreased because they are normally bound to albumin and albumin is lost into the urine. The activity of lecithin cholesterol acyltransferase (LCAT) is usually decreased. 

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. 

ApoE-containing VLDL in hyperlipidemic subjects has been shown to be both the product of particles less rich in apoE (as judged by the apoE apoC ratio) and the precursor of apoE-rich intermediate-density lipoprotein (N2). In cholesterol-fed dogs (F5) and humans with Type III hyperlipoproteinemia (F5, K3) there is evidence (based on the form of apoB, B-48, or B-100, and the response to fasting) that apoE-rich (3-VLDL contains remnants of both VLDL and chylomicrons. 

The use of plant sterols—(3-sitostcrol and sitostanol in consumer products to decrease cholesterol is supported by numerous clinical studies that document their efficacy in lowering mild hyperlipidemia (Jones et al., 1998 Hallikainen and Uusitupa, 1999). Although the normal diet contains plant sterols that range from 160 to 360 mg/day, a 5- to 10-fold increase is required to exert a cholesterol-lowering effect. Consumer products with increased amounts of phytosterols that exceed the content found in the diet have been made available to the consumer. In evaluating the efficacy of including sitostanol ester in margarine as a dietary supplement for children with familial hypercholesterolemia (FH), it was found that serum total cholesterol (TC), intermediate density lipoprotein-cholesterol and LDL-cholesterol levels fell while the HDL-cholesterol/LDL-cholesterol ratio was elevated. 

Triacylglycerols and cholesterol are exported from the liver as nascent VLDL complexes, destined primarily to muscle and adipose tissues. The VLDL complex contains apolipoprotein B-lOO and acquires C-I, C-II, C-III and E from circulating HDL complexes. Fatty acids are released from VLDLs in the same way as chylomicrons, through the action of LPL. This action, coupled to a loss of certain apoproteins (the apo-Cs), converts VLDLs to intermediate-density lipoproteins (IDLs), also termed VLDL remnants. The apo-Cs are transferred to HDLs. The predominant remaining proteins are apo-B-100 and apo-E. Further loss of triacylglycerols converts IDLs to LDLs. 

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. 

Intermediate-density lipoprotein Endogenous cholesterol esters (IDL)... 

Remnant removal disease (RRD, also called remnant lipaemia, familial dysbetalipoproteinemia) (uncommon) in which there is a defect of apolipoprotein E. This is the major ligand that allows internalisation and subsequent metabolism of remnant particles derived from VLDL and chylomicrons. The consequence is accumulation of VLDL remnants called intermediate density lipoprotein (IDL) with cholesterol and triglycerides usually in the range 6-9 mmol/1. Patients experience severe macrovascular disease (as above). 

Although apoE was recognized first as a component of VLDLs (Shore and Shore, 1973 Shelburne and Quarfordt, 1974 Utermann, 1975 Kane et al., 1975), it has been demonstrated to be present in most other lipoprotein classes as well. In addition to occurring in the other triglyceride-rich lipoproteins, chylomicrons and their remnants, and the intermediate-density lipoproteins (IDEs), apoE is present in a subclass of the cholesterol-rich high-density lipoproteins (HDLs), referred to as HDL-with apoE (Mahley, 1978). By use of SDS-PAGE (Fig. 6), the Mr 34,200 apoE is easily distinguished from the other common apolipoproteins that also are present in the various human lipoprotein classes. 

Cholesterol and triglycerides circulate as part of lipoprotein complexes throughout the bloodstream. These complexes can be separated via ultracentrifugation into HDL, intermediate-density lipoprotein (IDL), LDL, and very-low-density lipoprotein (VLDL) fractions. In the liver, cholesterol and TG are synthesized, incorporated into VLDL, and released into the plasma for delivery to peripheral tissues. 

VLDL> Very low-density lipoproteins IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, iiigh-density lipoproteins Lp(a), lipoprotein(a) LCAT, lecithin cholesterol acyltransferase LPL, lipoprotein lipase. 

Figure 26-19 Endogenous lipoprotein metabolism pathway. TG, Triglyceride CE, cholesterol ester FC, free cholesterol PL, phospholipids HDL, high-density lipoproteins LDL low-density lipoproteins IDL, intermediate-density lipoproteins VLDL very low-density lipoproteins FA, fatty acid LPL, lipoprotein lipase LCAL lecithin cholesterol acyltransferase B, apolipoproteln B-tOO A, apolipoprotein A-l C, apolipoprotein C-fl , apofipoprotein E. (From RIfai N. Lipoproteins and apolipoproteins Composition, metabolism, and association with coronary heart disease. Arch Pathol Lab Med 1986 110 694-701. Copyright 1986, American Medical Association.)...

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.)...

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