Chylomicrons Subject

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. 

Plasma lipoproteins can be divided into six major classes (see Fig. 5.2.1). Four of these classes derive from the liver and are present in the plasma of fasted subjects very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The other two classes of lipoproteins derive from the intestine and are found in the plasma of nor-molipidemic individuals only after a fatty meal (postprandially) chylomicrons and chylomicron remnants. 

ApoA-IV is an immunologically distinct apolipoprotein of Mr 46,000 (B22, G28, W7). It has been demonstrated in intestinal epithelial cells from fasting subjects and a marked increase has been shown during lipid absorption (G27). About 10-13% of chylomicron apolipoprotein and 24-30% of intestinal VLDL apolipoprotein is apoA-IV. In fasting plasma, 98% of apoA-IV is in the d> 1.21 g/ml fraction and in lipemic plasma 90% is in this fraction, while 10% is associated with triglyceride-rich lipoproteins (G27). Gel permeation chromatography confirmed that in plasma most apoA-IV is free, unassociated with lipoproteins (B22, G27). 

Kinetic studies in normal human subjects show that 70—100% of the apoB of VLDL is converted to LDL apoB, and alll LDL apoB is derived from VLDL (B31, PI, R5, S35). When radiolabeled chylomicrons were reinfused into a subject with failure of apoB-100 production, the plasma half-life of the apoB-48 was 50 minutes, with no conversion to LDL (M20, M21). Studies on subjects with hypertriglyceridemia have suggested that up to two-thirds VLDL-apoB is removed from the circulation as IDL-sized particles and not metabolized to form LDL (F16, R5). However, VLDL may be heterogeneous in several respects. The VLDL fraction of fasted individuals with hypertriglyceridemia may contain both apoB-100 and apoB-48 (K2). VLDL... 

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. 

Chylomicrons are triglyceride rich and contain apolipoprotein B-48 and the A types. The latter are synthesized in the intestinal tract cells. Additional apoproteins are transferred to the chylomicrons from HDL in circulation the apoE and apoC types. Their site of synthesis is the liver. The chylomicrons are subject to degradation by lipoprotein lipase in the peripheral tissue, especially adipose tissue. Lipoprotein lipase activity is increased by increased blood insulin levels. This enzyme is extracellular, attached to the capillary endothelial cells, and activated by ApoC-II, which is present in the chylomicrons. Lipoprotein lipase causes the hydrolysis of triglycerides, thus decreasing chylomicron size... 

Type I lipoproteinemia is generally caused by the inability of the organism to clear chylomicrons. The problem may be defective ApoC-II or a defective lipoprotein lipase. Very often, chylomicron clearance may be affected by injection of heparin, which apparently releases hepatic lipase from the liver into the circulation. ApoE disorders may be associated with type III lipoproteinemia, in which clearance of IDL is impeded. Increases in circulatory LDL are usually caused by a decrease in tissue receptors specific for ApoB-100. An extreme case of type Ha hyperlipoproteinemia is familial hypercholesterolemia, in which serum cholesterol levels may be as high as 1000 mg/dL and the subjects may die in adolescence from cardiovascular disease. There is total absence of ApoB-100 receptors. Mild type Ila and lib lipoproteinemias are the most commonly occurring primary lipoproteinemias in the general population. 

The liver requires cholesterol for synthesizing VLDL particles and bile acids. Trigly-ceride-rich VLDL particles are released into the blood and, like the chylomicrons, supply Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

As discussed in Section 2.2.2.2, only a relatively small proportion of carotene undergoes oxidation in the intestinal mucosa, and a significant amount of carotene enters the circulation in chylomicrons. Novotny and coworkers (1995) reported a study in one subject given an oral dose of pff]/3-carotene dissolved in oU 22% was absorbed - 17.8% as carotene and 4.2% as retinoids. Their results suggest that nonintestinal carotene dioxygenase is important in retinoid formation, because there was a late disappearance of labeled carotene from the circulation and the appearance of labeled retinoids. 

The Relative Dose Response (RDR) Test The RDR test is a test of the ahUity of a dose of vitamin A to raise the plasma concentration of retinol several hours later, after chylomicrons have heen cleared from the circulation. What is being tested is the ahUity of the liver to release retinol into the circulation. In subjects who are retinol deficient, a test dose will produce a large increase in plasma retinol, because of the accumulation of apo-RBP in the liver in deficiency (Section 2.2.3). In those whose problem is due to lack of RBP, then little of the dose will be released into the circulation. An RDR greater than 20% indicates depletion of liver reserves of retinol to less than 70 /rmol per kg (Underwood, 1990). 

Measurement of the plasma concentration of phylloquinone gives some information about stams, but reflects not only intake but also plasma triacyl-glycerol, because most is carried in chylomicrons and chylomicron remnants. The plasma concentration of phylloquinone is higher in older subjects, but the phylloquinone triacylglycerol ratio is lower than in younger people (Booth andSuttie, 1998). 

At what time after breakfast did the plasma of the normal subjects scatter the most light (Figure 6-24) State evidence that the disease hyperlipoproteinemia involves defects in the ability of tissues of the body to process chylomicrons-... 

Figure 6.Z7 presents data from a molecular sieve chromatographic. separation of plasma proteins according to their molecular weights. This experiment supplies evidence that the change in location of apo E resulted from transfer of this protein from HDI-s to chylomicrons. The data show that, in the fasting subject ( ), the amount of apo F associated with HDLs was somewhat greater than that associated with chylomicrons. However, with com oil feeding (O), the amount of apo E...

In this study, blood samples taken before and after human subjects consumed a breakfast of com oil (100 g) were analyzed for the total TG and apo E content. A more subtle parameter was measured also, namely the proportion of apo E associated with HDLs and with chylomicrons. This parameter can be measured by molecular sieve chromatography. (Details of this method are presented in the next section.) Results from three normal subjects appear in Table 6.7. The data in Table 6.7 demonstrate that the plasma TG levels increased postprandially (after eating), as expected. The data a show that the overall concentration of apo E in the bloodstream was fairly constant before and after eating. This constancy should not be interpreted to mean that apo E is not changing in any way. The proportion of... 

Subject Total TGs (mg/100 ml plasma) ApoE ( ig/100 ml plasma) Apo E with chylomicrons (%)... 

Lipoprotein and hepatic lipases are important enzymes involved in the metabolism of chylomicrons and various fractions of lipoproteins. Both have been the subject of attention, as evidenced by numerous reviews (e.g., Garfinkel and Schotz, 1987 Wang eta/., 1992). This interest stems from the fact that abnormal lipoprotein metabolism has been linked to various disorders, including hyperchylomicronemia, hypercholesterolemia, hypertriglyceridemia, obesity, diabetes, and premature atherosclerosis. Genetic defects in both HL and LPL are now known to be the cause of at least some familial disorders of lipoprotein metabolism. 

The CDC has also defined a reference method for LDL cholesterol based on the same techniques described above for HDL cholesterol. After ultracentrifugation to remove the VLDL and any chylomicrons present, the bottom fraction (d > 1.006) is subjected to precipitation by heparin and manganese as described previously. After measurement of cholesterol in the d > 1.006 fraction and in the heparin-Mn supernatant solution, LDL cholesterol is calculated by difference. It should be noted that the LDL fraction as measured by this reference method is a so-called broad-cut fraction including any IDL and Lp(a). 

Apo C-II, the activator of lipoprotein lipase, was absent in a subject with severe hypertriglyceridemia a transfusion of plasma produced a temporary fall In the patient s circulating triglyceride, due to apo C-II in the normal donor s plasma. It was also reported that NA (12 g/day) Increased apo C-II in chylomicrons and VLDL of a subject with Type V hyperlipoproteinemia." These studies support the concept that low amounts of apo C-II may play a role in the development of hypertrigly-cerIdemia. 

Apo-E (chylomicron remnant) Liver Chylomicron remnants HDL-with apo-E (HDL ) Apo-E Not subject to marked down-regulation Uptake of chylomicron remnants and cholesterol-loaded HDL-with-apo-E Delivery of cholesterol to the liver for excretion... 

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