Lipoproteins plasma, ApoE

Apo(a) is a carbohydrate-rich protein found in a lipoprotein with a slightly higher density than LDL (1.025-1,125 g/ml) (S19, S37). Lp(a) lipoprotein contains apo(a), together with apoB and small amounts of apoA-III (J10) [or perhaps small amounts of albumin and apoC (S21)]. Albers et al. found that apo(a) levels in plasma were not correlated with apoB, and changes in apoB concentration were not reflected in changes in apo(a) (All). Lp(a) seems... 

Fig. 12. Distribution of 1-labeled apoE4, apoE3, and apoE2 among plasma lipoproteins. lodinated apoE was incubated with plasma for 2 hr at 37°C. The plasma was then subjected to agarose chromatography on Bio-Gel A-5m. Arrows indicate the elution positions of VLDL, LDL, and HDL. From Weisgraber et al. (1990).

VLDL secretion can also be studied in vivo by injection of mice or rats with the detergent Triton WR1339 or poloxmer. These compounds block the lipolysis of TG-rich lipoproteins in plasma so that the amount of plasma apo B-containing lipoproteins reflects only the secretion of apo B, in the absence of lipolysis. This methodology has some limitations, primarily because neither detergent is specific for blocking VLDL lipolysis (J.T. Billheimer, 2005). 

Complete elimination of MTP is embryonically lethal in mice because, unlike the situation in humans, apo B-containing lipoproteins are required for transferring lipids from the yolk sac to the developing mouse embryo [14]. However, when the Mtp gene was inactivated specifically in the liver, the mice were viable. In addition, the amount of plasma apo BlOO was reduced by >90% compared to that in wild-type mice whereas, surprisingly, apo B48 was only slightly reduced [14]. Consistent with these observations, apo BlOO... 

Another plasma protein that is involved in lipoprotein metabolism is apolipoprotein M. Apo M is a small (22 kDa) apolipoprotein mainly associated with HDLs [21]. Levels of apo M in human plasma (20-35 pg/ml or less than) are similar to those of apo A2, the second most abundant HDL protein in the circulation. In apo M knock-out mice, pre-beta-HDL is undetectable. These mice accumulated abnormally large plasma HDLs and showed increased susceptibility to atherosclerosis. Apo M over-expression in mice was associated with increased pre-beta,-HDL levels in plasma. Apo M in the circulation retains an uncleaved hydrophobic leader sequence that may play a role in anchoring this protein to HDLs. The molar concentration of apo M in plasma is similar to that of apo A1 in pre-beta,-HDLs. Partial displacement of apo A1 by apo M on the surface of large HDLs may be sufficient to stimulate RCT. Direct evidence for a role of apo M in human apo A1 recycling is, however, presently lacking. 

ApoE plays a major role in the metabolism of triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, VLDL, and IDL) and in the local redistribution of lipids among cells. About half of the plasma apoE in fasting subjects is associated with triglyceride-rich lipoproteins the other half is a constituent of HDL. 

Several lines of evidence have implicated apolipoprotein (apo) C-III in plasma TG metabolism. Reports have indicated that apo C-III inhibits TG hydrolysis by LPL and hepatic lipase in vitro and impairs the uptake of TG-rieh lipoproteins hy the liver. Moreover, transgenic animal studies, in whieh the plasma TG levels are proportional to plasma apo C-III concentrations and liver apo C-III gene expression, provided more direct evidence for the causal involvement of apo C-III in h5 ertriglyeeridemia. Recently, it has been shown that fibrate downregulates apo C-III e qiression (Table 1) and this may contribute for the hypotriglyceridemic action of these drugs. ... 

After synthesis in enterocytes (increasing in response to intestinal lipid absorption) Apo A-IV is secreted as a major apoprotein component of chylomicrons and is transported in the lymph ducts (for review see [17]). Upon entry into the blood plasma compartment, it rapidly dissociates from chylomicrons and is found in the lipoprotein-free plasma fraction. Weinberg und Spector [38] showed a difference in isoform distribution between lymph and plasma Apo A-IV. Treatment of lymph Apo A-IV with neuraminidase could not mimic the isopeptide change seen upon entry into the plasma compartment [38]. The authors showed that changes in Apo A-IV isoform... 

Several pools of plasma Apo A-IV were postulated, mainly from distribution and metabolic studies including tracer kinetics [15, 24]. The pools consist of Apo A-IV associated with lipoproteins of very low density, namely chylomicrons, with HDL, and in the lipoprotein-free fraction, and evidence was obtained for compartmentaliza-tion of Apo A-IV in HDL and the lipoprotein-free fraction [15],... 

The possible mechanism of Apo A-IV displacement from the surface of chylomicrons upon entry into the plasma was studied in an in vitro model by Weinberg and Spector [41]. They used Apo A-IV associated with a phospholipid-triglyceride emulsion for displacement studies. When these chylomicron-like particles were incubated with HDL, they found a displacement of Apo A-IV from these particles, mainly by Apo C-III. Thus, one of the mechanisms responsible for the dissociation of Apo A-IV frbm chylomicrons upon entry into the plasma compartment could be a displacement by other circulating apoproteins that have a higher affinity for chylomicrons (or their remnants after attack by hpoprotein lipase). In contrast to Apo A-IV, which decays and is later mostly found in the lipoprotein-free plasma compartment, the other major chylomicron apoprotein, A-I, reassociates with HDL, as shown by tracer kinetic studies [20, 29]. It thus remains puzzling why the bulk of Apo A-IV, despite its apoprotein structure, does not reassociate with lipoproteins. In addition, lymph and plasma Apo A-IV have similar a-helical contents and properties in solution [10]. This seems to be an unexplained phenomenon since we were able to show that apoprotein A-IV, isolated either from chylomicrons or from lipoprotein-free plasma, recombines with hpids to form stable complexes [34]. 

Bittolo Bon G, Cazzolato G, Saccardi M, Kostner GM, Avogaro P (1984) Total plasma ApoE and high density lipoprotein ApoE in survivors of myocardial infarction. Atherosclerosis 53 69-75... 

The surface of the lipoproteins in plasma contains the apolipoproteins which determine the ultimate fate of the individual lipoproteins due to their interaction with enzymes and receptors on various cells in the body. The clearance of LDL from plasma is accomplished via the interaction of apo B on LDL with the LDL receptor on various peripheral tissues and liver. Apo B is also considered a risk factor for coronary heart disease (Sniderman, 1988). The presence of apo Ai on the surface of HDL may account for the protective role of this lipoprotein. The apo B/apo Aj ratio may be a better indicator of risk than apo B alone (Thompson, 1984). 

LCAT deficiency in LDLr-/- mice and Apo E -/- mice fed an atherogenic diet, resulted in aortic cholesterol deposition likely caused by a reduction in plasma HDL, increased saturation of CE in apo B lipoproteins, and in the Apo E -/- background, increased plasma Apo B lipoprotein concentration (470). LCAT-deficient mice are associated with an increase in oxidative stress that is paradoxically reversed in a hyperlipidemic background possibly caused by the redistribution of paraoxonase (PON) to the non-HDL fraction. This may in part contribute to the reduced atherosclerosis seen in Apo E -/- xLCAT -/- mice (this could explain the surprising finding that LCAT-deficient subjects have severe hypoalphalipoproteinemia yet are not prone to premature CHD) (477). 

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... 

Modified procedure HDL plasma—plasma depleted with apo B-con-taining lipoproteins by pretreatment with dextran sulfate/Mg2+ HDL reagent (Sigma, procedure 352-3). Plasma LDL-bound antiradical parameters can be calculated as the difference between ACW/ACL/ACL0 for whole plasma and for HDL plasma as well. 

Several clinical studies revealed that administration of fenofibrate produces reductions in total-C, LDL-C, apo B, total triglycerides, and triglyceride-rich (very low density) lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in HDL-C, apo AI, and apo AIL However, since fenofibrate is rapidly converted to fenofibric acid during absorption and fenofibric acid, but not fenofibrate, is found circulating in plasma, the effects of fenofibric acid have been extensively evaluated in these studies. 

Similar problems occur for the nephelometric and turbidimetric methods, where the sizes of the IgG-Lp(a) complexes depend upon that of apo(a) itself (L2, W4). Furthermore, problems due to interferences from elevated plasma triglyceride are commonly encountered in the precipitation techniques (C3). As Lp(a) can be redistributed among the Lp(a) fraction and the triglyceride-rich lipoproteins, especially in patients after a fatty meal (B11), these methods are not appropriate for monitoring Lp(a) levels and distribution in plasma. 

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