Cholesterol transport, ApoE

HDLs are the smallest of the lipoproteins. The HDL particle is synthesized mainly by the liver, and also by the intestines. When excess cholesterol occurs in extra-hepatic bsEues, it is picked up by HDLs by a process called reverse cholesterol transport. Apo A-I is the vital and defining protein of the HDL. Each HDL particle contains 2-4 molecules of Apo A-I, When secreted by the liver, HDLs are lipid-poor... 

HDL concentrations vary reciprocally with plasma triacylglycerol concentrations and directly with the activity of lipoprotein lipase. This may be due to surplus surface constituents, eg, phospholipid and apo A-I being released during hydrolysis of chylomicrons and VLDL and contributing toward the formation of preP-HDL and discoidal HDL. HDLj concentrations are inversely related to the incidence of coronary atherosclerosis, possibly because they reflect the efficiency of reverse cholesterol transport. HDL, (HDLj) is found in... 

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

Apolipoprotein E (ApoE) A protein involved in cholesterol transport that has three major isoforms, one of which, ApoE4, significantly increases the risk of developing Alzheimer s disease. 

After triglyceride is removed from the VLDL, the resulting partide is referred to as either a VLDL remnant or as an IDL. A portion of the IDLs are picked up by hepatocytes through their apoE receptor, but some of the IDLs remain in the blood, where they are further metabolized. These IDLs are transition particles between triglyceride and cholesterol transport. In the blood, they can acquire cholesterol transferred from HDL particles and thus become converted into LDLs, as shown in Figure 1-15-6. 

The HDL may subsequently be picked up by the liver throu the apoE receptor or deliver cholesterol throi the scavenger receptor SR-Bl (reverse cholesterol transport firom the periphery to the liver). The HDL may also transfer the cholesterol to an IDL reforming a normal, unoxidized LDL particle. 

Apo B is structural apolipoprotein for chylomicrons and for VLDL and LDL particles. It is synthesized in enteric and hepatic cells. It is important for cholesterol transport to cells via interaction with LDL receptors. 

Apolipoprotein B. Apo B is a structural apolipoprotein for chylomicrons, VLDL, and LDL particles. It is synthesized in enteric and hepatic cells. It is important for cholesterol transport to cells via interaction with LDL receptors. Nowadays, it seems its clinical relevance in CSF investigation is near Apo A-I and Apo A-II, but in current studies some varieties can be found (A23, T3). 

Until 1993 apolipoprotein E was best known for its central role in plasma lipoproteins and cholesterol transport (Fig. 21-1). However, one of the three common alleles of the apoE gene confers a significant risk of development of Alzheimer disease.12171218 A high blood cholesterol level is also correlated with increased risk.12191220 Membrane abnormalities in mitochondria have been associated with Alzheimer disease.1221 Also related to membranes and lipid metabolism, vitamin E appears to combat Alzheimer disease.843 1218... 

Genes coding for APO-E are associated with different risks for Alzheimer s disease. There are three alleles (or copies) of the gene coding for this apolipoprotein which are called E2, E3, and E4. For example, a gene on chromosome 19 that codes for APO-E is linked to many cases of late-onset Alzheimer s disease. Moreover, APO-E is associated with cholesterol transport and involved with other neuronal functions, including repair, growth, and maintenance of myelin sheaths and cell membranes. 

Figure 5.6 General scheme of lipoprotein metabolism. Triacylglycerols and cholesterol are exported from the liver in VLDLs, containing apolipoprotein B-lOO they further acquire apo-C-I, II, III and apo-E from circulating HDL. Apo-C-II activates lipoprotein lipase to remove fatty acids from VLDLs. As triacylglycerols are removed, VLDLs transform to IDEs and finally LDLs. LDLs are the main vehicle for transfer of cholesterol to the tissues uptake of LDL occurs primarily in the liver through LDL-receptor-mediated endocytosis, which requires the presence of apo-B-100. HDLs are synthesised essentially devoid of cholesterol or triacylglycerol and provide a circulating source of apo-C-I, II and apo-E. HDLs gradually accumulate cholesteryl esters, eventually returning these to the liver, mediated by an apo-A-I receptor this is referred to as reverse cholesterol transport. ...

Reverse cholesterol transport stimulation fHDL, fapo Al, fABC transporter, 4,CETP LDL reduction Anti-Apo B,... 

In addition, in species with high concentrations of HDL-with apoE, it has been postulated that this lipoprotein class serves to transport excess cholesterol from peripheral cells to the liver for elimination from the body (Mahley et al, 1980). This transport process is referred to as the reverse cholesterol transport process (Glomset, 1968). In contrast, in species with high CETP activity, the excess cholesterol from the periphery is transferred from the typical non-apoE-containing HDL to the lower density lipoprotein classes (VLDL, IDL, and LDL) for clearance by the liver. 

Apolipoprotein (apo) A-I expression was demonstrated in porcine brain capillaries, suggesting an independent lipid metabolism inthebrain(151). Apo A-Iisthe major protein component of HDLs, which are responsible for reverse cholesterol transport from various tissues to the liver via the SR-BI receptor. Further research indicated that apo A-I was effluxed by porcine BCEC, whereas aortic endothelial cells did not. In addition, apo A-I-inducing compounds, such as cholesterol,... 

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.)...

Initial interest in cholesterol and Alzheimer s disease stemmed from a lengthy historical backdrop. One of the first studies hnking cholesterol to AD stemmed from an observation that senile plaques were quite prevalent in the brains of non-demented patients who had died from coronary heart disease [21], a population known to possess elevated cholesterol levels. Additional studies soon followed demonstrating that the ApoE4 allele of the ApoE cholesterol transporter was a major risk factor for AD [ 13 -16]. Is there a clear association between cholesterol and Alzheimer s disease ... 

The laws of mass action govern the interactions of lipids and most apoproteins in lipoproteins, so that as the affinities between surface components change dining lipoprotein metabolism, apoproteins may dissociate from one particle and bind to another. In fact, all of the apoproteins, with the possible exception of apoprotein B (apo B), can change their lipoprotein associations. The reason for the unique behavior of apo B remains a mystery. On the basis of their principal transport function, lipoproteins may be divided into two classes according to the composition of their major core lipids. The principal triacylglycerol carriers are chylomicrons and very-low-density lipoproteins (VLDLs), whereas most cholesterol transport occurs via LDLs and HDLs. 

HDL is antiatherogenic and removes cholesterol from peripheral cells and tissues for eventual transport to hepatocytes and excretion in the bile directly or after conversion into bile acids. The efflux of cholesterol from peripheral cells is mediated by the ATP-binding cassette (ABC) transporter protein (discussed later). The flux of cholesterol transport from extrahepatic tissues (e.g., blood vessel wall) toward liver for excretion is known as the reverse cholesterol transport pathway. In contrast, the forward cholesterol pathway involves the transport of cholesterol from liver to the peripheral cells and tissues via the VLDL IDL LDL pathway. It should be noted, however, that the liver plays a major role in the removal of these lipoproteins. Thus, the system of reverse cholesterol transport consisting of LCAT, CETP, apo D, and their carrier lipoproteins is critical for maintaining cellular cholesterol homeostasis. The role of CETP is exemplified in clinical studies involving patients with polymorphic... 

Plasma contains several apolipoproteins, involved in lipid and cholesterol transport. Several have been reported to be glycosylated in low amounts including apoB, apoE and apoC-llI [26]. ApoB contains about 2-2.5% carbohydrate as complex-type N-glycan whereas apoE appears to contain O-linked glycan [27]. ApoE is synthesized in sialylated form but in plasma it is 80% desialylated. 

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