Apolipoprotein B-100

Lipoprotein fraction containing triglycerides and to a lesser degree cholesterol. VLDL is produced by the liver. The main structural protein connected to this lipoprotein class is apolipoprotein B. 

Figure 25-2. The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low density lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum SER, smooth endoplasmic reticulum G, Golgi apparatus N, nucleus C, chylomicrons VLDL, very low density lipoproteins E, endothelium SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A B-48, apolipoprotein B-48 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylgiycerol C, cholesterol and cholesteryl ester P, phospholipid HL, hepatic lipase LRP, LDL receptor-reiated protein.) Only the predominant lipids are shown.

In this in vitro system, the presence of serum in cell culture medium is not necessary, but the type of transwell is important (the total amount of H-triglycerides secreted was two-fold higher when using 3 pm versus 1 pm pore size transwells), and oleic acid supplementation is required for the formation and secretion of CMs as well as the transport of 3-carotene through Caco-2 cells. Finally, the presence of Tween 40 does not affect CM synthesis and secretion in this in vitro cell culture system. Thus, CMs secreted by Caco-2 cells were characterized as particles rich in newly synthesized H-triglycerides (90% of total secreted) containing apolipoprotein B (30% of total secreted) and H-phospholipids (20% of total secreted) and with an average diameter of 60 nm. These characteristics are close to those of CMs secreted in vivo by enterocytes. ... 

Steinbrecher, U.P. (1987). Oxidation of human low density lipoprotein results in derivatisation of lysine residues of apolipoprotein B by lipid peroxidation decomposition products. J. Biol. Chem. 262, 3603-3608. 

In contrast to MDA and hydroxynonenai, other aldehyde products of lipid peroxidation are hydrophobic and remain closely associated with LDL to accumulate to mil-limolar concentrations. Aldehydes at these elevated levels react with the protein portion of the LDL molecule, apolipoprotein B (apoB). Accumulated aldehydes bind the free amino groups from lysine residues in addition to other functional groups (-OH, -SH) on the apoB polypeptide. Consequently, the protein takes on a net negative charge and complete structural rearrangement results in the formation of ox-LDL. ox-LDL is no longer recognized by the LDL receptor, and has several pro-inflammatory properties (discussed below). 

Alphafoetoprotein, Ancrod, Anti-D Immunoglobulin, Antithrombin III total, Apolipoprotein B, Haemoglobin A2 and F Lysate, Heparin, Protamine Protein C, Fibrinogen, Plasmin a-Thrombin, Antithrombins, (3-Thromboglobulin, Haemiglo-bincyanide... 

Baba, Y., Tomisaki, R., Sumita, C., Morimoto, I., Sugita, S., Tsuhako, M., Miki, T., and Ogihara, T., Rapid typing of variable number of tandem repeat locus in the human apolipoprotein B gene for DNA diagnosis of heart disease by polymerase chain reaction and capillary electrophoresis, Electrophoresis, 16, 1437, 1995. 

Each lipoprotein has various proteins called apolipoproteins embedded on the surface (Fig. 9-1). These apolipoproteins serve four main purposes, they (1) are required for assembly and secretion of lipoproteins (such as apolipoproteins B-48 and B-100) (2) serve as major structural components of lipoproteins ... 

In the liver, cholesterol and triglycerides are incorporated into VLDL along with phospholipids and apolipoprotein B-100... 

Fig. 9-4). Very low-density lipoprotein particles are released into the circulation where they acquire apolipoprotein E and apolipoprotein C-II from HDL. Very-low density lipoprotein loses its triglyceride content through the interaction with LPL to form VLDL remnant and IDL. Intermediate-density lipoprotein can be cleared from the circulation by hepatic LDL receptors or further converted to LDL (by further depletion of triglycerides) through the action of hepatic lipases (HL). Approximately 50% of IDL is converted to LDL. Low-density lipoprotein particles are cleared from the circulation primarily by hepatic LDL receptors by interaction with apolipoprotein B-100. They can also be taken up by extra-hepatic tissues or enter the arterial wall, contributing to atherogenesis.4,6... 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

Fibrates work by reducing apolipoproteins B, C-III (an inhibitor of LPL), and E, and increasing apolipoproteins A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-a), a nuclear receptor involved in cellular function. The changes in these apolipoproteins result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL. 

Omega-3 fatty acids (eicosapentaenoic acid and docosa-hexaenoic acid), the predominant fatty acids in the oil of cold-water fish, lower triglycerides by as much as 35% when taken in large amounts. Fish oil supplements may be useful for patients with high triglycerides despite diet, alcohol restriction, and fibrate therapy. This effect may be modulated thru PPAR-a and a reduction in apolipoprotein B-100 secretion. Omega-3 fatty acids reduce platelet aggregation and have... 

Gosling J, Slaymaker S, Gu L, et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 1999 103(6) 773-778. 

Malek, G, Li, CM, Guidry, C, Medeiros, NE, and Curcio, CA, 2003. Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy. Am J Pathol 162, 413425. 

Aalto-Setala K, Kontula K, Manttari M, Huttunen J, Manninen V, Koski-nen P, et al. DNA polymorphisms of apolipoprotein B and AI/CIII genes and response to gemfibrozil treatment. Clin Pharmacol Ther 1991 50 208-214. 

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989 86 587-591. 

Marz W, Baumstark M, Scharnagl H, Ruzicka V, Buxbaum S, Herwig J, et al. Accumulation of small dense low density lipoproteins in a homozygous patient with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor. J Clin Invest 1993 92 2922-2933. 

Myant NB. Familial defective apolipoprotein B-100 a review, including some comparisons with familial hypercholesterolaemia [published erratum appears in Atherosclerosis 1994 Feb 105[2] 253[. Atherosclerosis 1993 104 1-18. 

Schaefer JR, Scharnagl H, Baumstark MW, Schweer H, Zech LA, Seyberth H, et al. Homozygous familial defective apolipoprotein B-100. Enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arter-ioscler Thromb Vase Biol 1997 17 348-353. 

Ojaia JP, Helve E, Ehnholm C, Aalto-Setaia K, Kontuia KK, Tikkanen MJ. Effect of apolipoprotein E polymorphism and Xbal polymorphism of apolipoprotein B on response to lovastatin treatment in familial and non-familial hy-percholesterolaemia. J Intern Med 1991 230 397-405. 

Recently, Batthyany et al. [133] pointed out that the reduction of cupric ions bound to apolipoprotein B-100 by endogenous LDL components might be an initiation step in copper-mediated LDL oxidation. They suggested that this reaction proceeds to form cuprous ion and the protein-tryptophanyl free radical the latter was identified on the basis of EPR spectrum with spin-trap 2-methyl-2-nitrosopropane. 

It follows from the above that MPO may catalyze the formation of chlorinated products in media containing chloride ions. Recently, Hazen et al. [172] have shown that the same enzyme catalyzes lipid peroxidation and protein nitration in media containing physiologically relevant levels of nitrite ions. It was found that the interaction of activated monocytes with LDL in the presence of nitrite ions resulted in the nitration of apolipoprotein B-100 tyrosine residues and the generation of lipid peroxidation products 9-hydroxy-10,12-octadecadienoate and 9-hydroxy-10,12-octadecadienoic acid. In this case there might be two mechanisms of MPO catalytic activity. At low rates of nitric oxide flux, the process was inhibited by catalase and MPO inhibitors but not SOD, suggesting the MPO initiation. 

Gemfibrozil reduces the synthesis of VLDL and, to a lesser extent, apolipoprotein B with a concurrent increase in the rate of removal of triglyceride-rich lipoproteins from plasma. Clofibrate is less effective than gemfibrozil or niacin in reducing VLDL production. 

More refined analyses have focused on changes in the ratio of serum concentration of apolipoprotein B, the common constituent in all lipoproteins comprising non-HDL cholesterol, to apoliprotein A, the apolipoprotein associated with HDL. Raloxifene was equivalent to HT in lowering the apolipoprotein B/apolipoprotein A ratio in one study (Anderson et al. 2001). 

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