Chylomicron production

Milk fat globule membrane (MFGM) emulsion was shown to enhance the absorption of epidermal growth factor (EGF) from the intestine, especially to intestinal lymph. The oral bioavailability of propanolol was shown to increase when administered in oleic acid and other lipid media. It is thought that the oleic acid forms an ion-pair with the drag and the entire complex is incorporated into chylomicrons. A further factor in the absorption enhancing effects may be that oleic acid per se stimulates chylomicron production. 

Without the enzyme microsomal triglyceride transfer protein (MTP), hepatic triglycerides cannot be transferred to apoB-100. Patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (VLDL, IDL, or LDL). MTP also plays a key role in the synthesis of chylomicrons in the intestine, and mutations of MTP that result in the inability of triglycerides to he transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorder abetalipoproteinemia. 

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

Chylomicrons leave the absorptive cell by way of exocytosis. Because they are unable to cross the basement membrane of the blood capillaries, the chylomicrons enter the lacteals, which are part of the lymphatic system. The vessels of the lymphatic system converge to form the thoracic duct that drains into the venous system near the heart. Therefore, unlike products of carbohydrate and protein digestion that are transported directly to the liver by way of the hepatic portal vein, absorbed lipids are diluted in the blood... 

Answer A. These are the clinical features of lipoprotein lipase deficiency (Type I lipopro-teinemia). LDL receptor defects would result in elevated LDLs. HMG-CoA reductase and ApoB-100 have no direct relationship to chylomicrons. ApoB-48 deficiency would result in decreased production of chylomicrons. 

LDL is catabolized chiefly in hepatocytes and other cells by receptor-mediated endocytosis. Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via IDL and chylomicrons. Unlike other cells,... 

When the diet contains more fatty acids than are needed immediately as fuel, they are converted to triacylglycerols in the liver and packaged with specific apolipoproteins into very-low-density lipoprotein (VLDL). Excess carbohydrate in the diet can also be converted to triacylglycerols in the liver and exported as VLDLs (Fig. 21-40a). In addition to triacylglycerols, VLDLs contain some cholesterol and cholesteryl esters, as well as apoB-100, apoC-I, apoC-II, apoC-III, and apo-E (Table 21-3). These lipoproteins are transported in the blood from the liver to muscle and adipose tissue, where activation of lipoprotein lipase by apoC-II causes the release of free fatty acids from the VLDL triacylglycerols. Adipocytes take up these fatty acids, reconvert them to triacylglycerols, and store the products in intracellular lipid droplets myocytes, in contrast, primarily oxidize the fatty acids to supply energy. Most VLDL remnants are removed from the circulation by hepatocytes. The uptake, like that for chylomicrons, is... 

Correct answer = A. Pancreatic lipase hydrolyzes dietary triacylglycerol primarily to 2-monoacylglycerol plus two fatty acids. These products of hydrolysis can be absorbed by the intestinal mucosal cells. Bile salts do not inhibit release of fatty acids from triacylglycerol, but rather are necessary for the proper solubilization and hydrolysis of dietary triacylglycerol in the small intestine. Short- and medium-chain length fatty acids enter the portal circulation after absorption from the small intestine. Synthesis of apolipoproteins, especially apo B-48, is essential for the assembly and secretion of chylomicrons. 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

The plasma lipoproteins are made mainly in the liver and intestine. In the rat, approximately 80% of the plasma apoproteins originate from the liver the rest are derived from the intestine. The components of chylomicrons, including apoproteins A-I, A-IV, and B-48 phospholipid cholesterol cholesteryl ester and triacylglycerols, are products of the intestinal cells. Chylomicrons are secreted into lymphatic capillaries, which eventually enter the bloodstream. The liver is the major source of VLDLs and HDLs. 

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. 

Vine, D.F., Croft, K.D., Beilin, L.J., Mamo, J.C.L. 1997. Absorption of dietary cholesterol oxidation products and incorporation into rat lymph chylomicrons. Lipids 32, 887-893. 

Cause is either increased production or decreased clearance of VLDL and chylomicrons. Usually a genetic defect. 

ACAT transfers amino-acyl groups from one molecule to another. ACAT is an important enzyme in bile acid synthesis, and catalyses the intracellular esterification of cholesterol and formation of cholesteryl esters. ACAT-mediated esterification of cholesterol limits its solubility in the cell membrane and thus promotes accumulation of cholesterol ester in the fat droplets within the cytoplasm this process is important in preventing the toxic accumulation of free cholesterol that would otherwise damage ceU-membrane structure and function. Most of the cholesterol absorbed during intestinal transport undergoes ACAT-mediated esterification before incorporation into chylomicrons. In the liver, ACAT-mediated esterification of cholesterol is involved in the production and release of apo-B-containing lipoproteins. 

At least 20 different apo-B gene mutations identified LDL concentrations 10-20% of normal VLDL slightly lower HDL normal All have reduced HDL concentrations no effect on chylomicron or VLDL production... 

We have found that exercised obese Zucker, lean Zucker, and Fischer 3A4 rats had lower plasma triglycerides than sedentary rats (71,72) (Tables IV and V). In Zucker rats this was due to a lower chylomicron triglyceride concentration. Hepatic VLDL triglyceride production, measured via a recycled in situ liver perfusion technique, did not differ between exercised and sedentary rats of each phenotype (data not shown). This suggests extrahepatlc mechanisms are predominant in the hypotriglycerldemlc action of exercise. 

In this study, both groups of exercised animals had lower plasma total cholesterol and chylomicron cholesterol than appropriate sedentary control animals (Table VI). Unexpectedly, plasma HDL cholesterol was also lower in both groups of exercised animals (Table VI). Together with the results obtained on hepatic HDL cholesterol production, these data demonstrate that plasma HDL cholesterol concentration reflects hepatic HDL cholesterol production in obese, but not in lean rats. 

Table VI. Plasma Total, Chylomicron, and HDL Cholesterol and Hepatic HDL Cholesterol Production In Lean and Obese Zucker Rats In Response to Exercise...

Insulin, among other things, also stimulates production of lipoprotein lipase (LPL). With insulin deficiency in diabetes, there is insufficient LPL to release fatty acids from the triglycerides of VLDL and chylomicrons (see Fig. 6.4), another reason for accumulating serum triglycerides, apart from increased VLDL production by the liver. 

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