Apo VLDL

Recently, it has been shown that fraction V of apo HDL, closely resembling the D polypeptides of apo VLDL, is moderately soluble in aqueous solutions of ethanol, a fact to be taken into consideration in the delipidation of serum lipoproteins with extracting mixtures containing this organic solvent. The relevance to recovery problems was pointed out previously (Sll). 

In the following sections we give an outline of specific methods that have been employed successfully in the fractionation and purification of the polypeptides of apo HDL and apo VLDL. We also provide some comments on apo LDL, the exact nature of which is still not unambiguously resolved. 

Although it has been shown that at least some of these polypeptides derive from exchange with the VLDL protein (E4, S22), a stringent chemical corroboration of these findings has not been published. Studies from these laboratories have now provided such a docmuentation at least in terms of polypeptides D, Dj, Dg, and D4 in apo VLDL (for properties, see below). Other minor polypeptides are also members of V, but their properties are still in the process of being defined (L2a). 

After total delipidation of the Lp (a)-lipoprotein, only apo VLDL is soluble in 0.9% NaCl and detectable by immunochemical means (S28). It therefore seems unlikely that the specific antigenic determinant of the Lp (a)-lipoprotein is located on or is part of the apo VLDL protein moiety. At present, the nature of the antigenic determinant of Lp(a)-lipoprotein is not known. 

Ovalbumin Conalbumin Ovomucoid Lysozyme Vitellogenin apo-VLDL Glucose-6-P-dehydrogenase Oviduct Oviduct (liver) Oviduct Oviduct Liver Liver Uterus Thyroid Hormones Carbamyl phosphate synthase Growth hormone Prolactin ( ) a-Glycerophosphate dehydrogenase Malic enzyme Liver Pituitary Pituitary Liver (mitochondria) Liver... 

Cervilla J, Prince M, Joels S, Russ C, Lovestone S. Genes related to vasculm disease (APOE, VLDL-R, DCP-1) and other vascular factors in late-life depression. Am J Geriatr Psychiatr 2004 12 202-210. 

The main apohpoprotein of LDL (P-lipopro-tein) is apohpoprotein B (B-lOO) and is found also in VLDL. Chylomicrons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-lOO is synthesized in the hver. Apo B-lOO is one of the longest single polypeptide chains known, having 4536 amino acids and a molecular mass of 550,000 Da. Apo B-48 (48% of B-lOO) is formed from the same mRNA as apo B-lOO after the introduction of a stop signal by an RNA editing enzyme. Apo C-1, C-11, and C-111 are smaller polypeptides (molecular mass 7000— 9000 Da) freely transferable between several different hpoproteins. Apo E is foimd in VLDL, HDL, chylomicrons, and chylomicron remnants it accounts for 5— 10% of total VLDL apohpoproteins in normal subjects. 

There are striking similarities in the mechanisms of formation of chylomicrons by intestinal cells and of VLDL by hepatic parenchymal cells (Figure 25—2), perhaps because—apart from the mammary gland—the intestine and liver are the only tissues from which particulate lipid is secreted. Newly secreted or nascent chylomicrons and VLDL contain only a small amount of apolipoproteins C and E, and the frill complement is acquired from HDL in the circulation (Figures 25—3 and 25-4). Apo B is essential for chylomicron and VLDL formation. In abetalipoproteinemia (a rare disease), lipoproteins containing apo B are not formed and lipid droplets accumulate in the intestine and liver. 

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). 

VLDL is the precursor of IDL, which is then converted to LDL. Only one molecule of apo B-lOO is present in each of these lipoprotein particles, and this is conserved during the transformations. Thus, each LDL particle is derived from only one VLDL particle (Figure 25-4). Two possible fates await IDL. It can be taken up by the liver directly via the LDL (apo B-lOO, E) receptor, or it is converted to LDL. In humans, a relatively large proportion forms LDL, accounting for the increased concentrations of LDL in humans compared with many other mammals. 

HDL is synthesized and secreted from both liver and intestine (Figure 25—5). However, apo C and apo E are synthesized in the liver and transferred from fiver HDL to intestinal HDL when the latter enters the plasma. A major function of HDL is to act as a repository for the apo C and apo E required in the metabohsm of chylomicrons and VLDL. Nascent HDL consists of discoid phosphohpid bilayers containing apo A and free cholesterol. These hpoproteins are similar to the particles found in the plasma of patients with a deficiency of the plasma enzyme lecithimcholesterol acyltransferase (LCAT) and in the plasma of patients with obstructive jaundice. LCAT—and the LCAT activator apo A-I— bind to the disk, and the surface phosphohpid and free cholesterol are converted into cholesteryl esters and... 

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.

Hypolipoproteinemias Abetaiipoproteinemia No chylomicrons, VLDL, or LDL are formed because of defect in the loading of apo B with lipid. Rare blood acylglycerols low intestine and liver accumulate acylglycerols. Intestinal malabsorption. Early death avoidable by administration of large doses of fat-soluble vitamins, particularly vitamin E. 

Hyperlipoproteinemias Famiiiai iipoprotein iipase deficiency (type i) Hypertriacylglycerolemia due to deficiency of LPL, abnormal LPL, or apo C-ll deficiency causing inactive LPL. Slow clearance of chylomicrons and VLDL. Low levels of LDL and HDL. No increased risk of coronary disease. 

Familial type III hyperlipoproteinemia (broad beta disease, remnant removal disease, familial dysbetalipoproteinemia) Deficiency in remnant clearance by the liver is due to abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor. Increase in chylomicron and VLDL remnants of density < 1.019 (P-VLDL). Causes hypercholesterolemia, xanthomas, and atherosclerosis. 

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. 

Apo, apolipoprotein C, cholesterol HDL, high-density lipoprotein LDL, low-density lipoprotein TG, triglyceride VLDL, very low-density lipoprotein. 

ApoC-I is expressed mainly in liver but also in lung, skin, testis, spleen, neural retina, and RPE. Its multiple functions include the activation of lecithin cholesterol acyltransferase (LCAT) and the inhibition, among others, of lipoprotein and hepatic lipases that hydrolyze triglycerides in particle cores. Notably, both LCAT and lipoprotein lipases are expressed in RPE and choroid (Li et al., 2006). Moreover ApoC-I has been shown to displace ApoE on the VLDL and LDL and thus hinder their binding and uptake via their corresponding receptors (Li et al., 2006). 

Apolipoprotein AIV (apo AIV) is produced in the intestine and is found in chylomicrons, VLDL and HDL. It may modulate enzymes involved in lipoprotein metabolism and may serve as a saturation signal [49]. In a study with 144 participants the apo AIV His360Glu polymorphism showed no significant effect on cholesterol lowering in response to statin therapy [50]. 

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. 

Parsy et al. (P6) observed abnormal metabolites of apo-B100-containing lipoproteins, linking these metabolites to accumulation of triglyceride-rich particles containing Lp(a). The excellent correlations found between Lp(a) concentrations and VLDL cholesterol and triglycerides support the hypothesis of a close link between Lp(a) and triglyceride-rich lipoproteins in nephrosis (S42). 

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