Chylomicrons assembly

Hussain MM, Kancha RK, Zhou Z, et al. Chylomicron assembly and catabolism role of apolipoproteins and receptors.Biochim BiophysActa 1300 151-170,1996. 

ApoB-48 Intestine 264,000 Chylomicrons Assembly and secretion of chylomicrons from small bowel... 

In the fed state, chylomicrons assembled in the small intestine (section 4.3.3.2) and very low-density lipoproteins exported from the liver (section 5.6.2.2) bind to the cell surface, where lipoprotein lipase catalyses hydrolysis of triacylglycerols to glycerol and free fatty acids. 

As previously reported by Murata et al. (1994), the decreased response of chylomicron TAG to dietary DAG in healthy humans may be due to a reduction of re-esterification and chylomicron assembly in the small intestine, or to a reduction of subsequent secretion of chylomicrons into the circulation. The dietary DAG used in the Taguchi et al. (2000) study described above was composed mainly of 1,3-isoforms. Based on the nature of gastric and pancreatic... 

FIGURE 24.3 (a) A duct at the junction of the pancreas and duodenum secretes pancreatic juice into the duodenum, the first portion of the small intestine, (b) Hydrolysis of triacylglycerols by pancreatic and intestinal lipases. Pancreatic lipases cleave fatty acids at the C-1 and C-3 positions. Resulting monoacylglycerols with fatty acids at C-2 are hydrolyzed by intestinal lipases. Fatty acids and monoacylglycerols are absorbed through the intestinal wall and assembled into lipoprotein aggregates termed chylomicrons (discussed in Chapter 25). 

HDL and VLDL are assembled primarily in the endoplasmic reticulum of the liver (with smaller amounts produced in the intestine), whereas chylomicrons form in the intestine. LDL is not synthesized directly, but is made from VLDL. LDL appears to be the major circulatory complex for cholesterol and cholesterol esters. The primary task of chylomicrons is to transport triacylglycerols. Despite all this, it is extremely important to note that each of these lipoprotein classes contains some of each type of lipid. The relative amounts of HDL and LDL are important in the disposition of cholesterol in the body and in the development of arterial plaques (Figure 25.36). The structures of the various... 

J. Luchoomun and M. M. Hussain, Assembly and secretion of chylomicrons by differentiated Caco-2 cells. Nascent triglycerides and preformed phospholipids are preferentially used for lipoprotein assembly, J. Biol. Chem. 274 (1999) 19565-19572. 

Chylomicrons are assembled from dietary triglyceride (containing predominantly the longer-chain fatty adds) and cholesterol esters by intestinal epithelial cells. The core lipid is surrounded by phospholipids similar to those found in cell membranes, which increase the solubility of chylomicrons in lymph and blood. ApoB-48 is attached and required for release from the epithelial cells into the lymphatics. 

The metabolism of VLDL is very similar to that of chylomicrons, the major difference being that VLDL are assembled in hepatocytes to transport triglyceride containing fatty acids newly synthesized from excess glucose, or retrieved from the chylomicron remnants, to adipose tissue and musde. ApoB-100 is added in the hepatocytes to mediate release into the blood. Like chylomicrons, VLDL acquire apoC-II and apoE from HDL in the blood, and are metabolized by lipoprotein lipase in adipose tissue and musde. 

In chylomicron retention disease (Anderson s disease) the secretory defect is restricted to intestinal apoB-containing lipoproteins (i.e., chylomicrons). This very rare recessively inherited disorder results from defects in a GTPase, Sarlb, which plays a critical role in the intracellular assembly and trafficking of chylomicrons. The affected patients present with fat malabsorption resulting in steatorrhea and deficiency of fat-soluble vitamins [46, 52, 54]. 

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. 

Chylomicrons are assembled in intestinal mucosal cells and cany dietary triacylglycerol, cholesterol, fat-soluble vitamins, and cholesteryl esters (plus additional lipids made in these cells) to the peripheral tissues (Figure 18.16). 

Assembly of chylomicrons The enzymes involved in triacylglycerol, cholesterol, and phospholipid synthesis are located in Ihe smooth ER. Assembly of the apolipoproteins and lipid into chylomicrons requires microsomal triacylglycerol transfer protein (see p. 229), which loads apo B-48 with lipid. This occurs during transition from the ER to the Golgi, where the particles are packaged in secretory vesicles. These fuse with the plasma membrane releasing the lipoproteins, which then enter the lymphatic system and, ultimately, the blood. 

The plasma lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They function to keep lipids (primarily triacylglyc-erol and cholesteryl esters) soluble as they transport them between tissues. Lipoproteins are composed of a neutral lipid core (containing triacylglycerol, cholesteryl esters, or both) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol. Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily, triacylglycerol) plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs, thus making the chylomicrons functional. Apo C-ll activates lipoprotein lipase, which degrades the... 

Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily triacylglycerol), plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs. This makes the chylomicrons functional. 

Unlike other lipoproteins, HDL particles are assembled outside of cells from lipids and proteins, some of which may be donated from chylomicrons (see Fig. 21-1) or other lipoprotein particles. HDL has a higher protein content than other lipoproteins and is more heterogeneous. The major HDL protein is apolipoprotein A-I, but many HDL particles also contain A-jj 205,208-210 ancj apolipoproteins A-IV, D, and E may also be present. A low plasma level of HDL cholesterol is associated with a high risk of atherosclerosis.205 207... 

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

See Fig. 6-4. The polar surface of the spherical particle renders the assembly soluble in water. This structure can be considered to be a tentative one only. The amount of polar material in chylomicrons and VLDL is astonishingly small. Moreover, when lipoproteins come into contact with the membranes of the cells of target tissue, the proteins remain soluble and do not become incorporated into the membrane. This suggests that the proteins of lipoproteins have unusual properties. It is known that several species of proteins (apoproteins AI, All. B4K, B1(K), Cl, CII, CIII, D, and E) occur. The amino acid sequences of some of them have been determined, and they possess hydrophobic regions i.e., they have properties suggesting that parts of their structure are compatible with hydrocarbons (e.g., TAGs and the tails of phospholipids). 

In this autosomal recessive disease, the disorder does not involve the gene on chromosome 2, which is responsible for apoprotein assembly, but the MTP gene (microsomal triglyceride transfer protein), which is localized on chromosome 4 q 22—24. In the endoplasmic reticulum, MTP transfers cholesterol esters, triglycerides and phospholipids to the nascent apoprotein B. This process is a prerequisite for the transport of the complete lipoproteins (e.g. chylomicrons, VLDL) to the Golgi complex and their secretion into the blood via subsequent exocytosis. In the case of MTP deficiency, lipoprotein particles are not secreted, with the result that any superfluous apoprotein B is broken down in the endoplasmic reticulum. (214, 216, 219, 220)... 

The fatty acids and monoacylglycerol are absorbed by the intestinal cells, converted to fatty acyl CoA and reassembled into triacylglycerols. The triacyl glycerols then assemble with phospholipids and lipoproteins to form chylomicrons for transport through the lymph and blood to the tissues. 

Special proteins, called apoLipoproteins, are required for handling and traruv port of lipid droplets. These proteins are synthesized on the ER and enter the lumen of the ER, where they are assembled into large macromolecular structures. The relevant proteins include apolipoprotein A apo A) and apo lipoprotein B (apo B), Apo A and apo B combine with lipid droplets to form structures called chylomicrons, microscopic particles with large cores of lipid coated with a thin shell of protein. The chylomicrons are transferred to secretory vesicles, which migrate through the cytoplasm to the basal membrane of the cell. Here the vesicles fuse with the membrane, resulhng in the expulsion of chylomicrons from the cell. (If the vesicles fused with the apical membrane of the enterocyte, the effect would be a futile transfer of the dietary lipids back to the lumen of the small intestine.)... 

Lipoproteins are assembled in two organs, the small intestine and the liver. The lipoproteins assembled in the intestine contain the lipids assimilated from the diet. These lipoproteins, called chylomicrons, leave the enterocyte and enter the bloodstream via the Lymphatic system. The lipoproteins assembled in the liver contain lipids originating from the bloodstream and from de novo synthesis in the liver. The term de novo simply means "newly made from simple components" as opposed to "acquired from the diet" or "recycled from preexisting complex components." These lipoproteins, called very-low-dcnslty lipoproteins (VLDLs), are secreted from the liver into the bloodstream. The liver also synthesizes and secretes other Lipoproteins called high-density Lipoproteins (HDLs), which interact with the chylomicrons and VLDLs in the bloodstream and promote their maturation and function. The data in Table 6-4 show that chylomicrons contain a small proportion of protein, whereas HDLs have a relatively high protein content. Of greater interest is the identity and function of the proteins that constitute these particles. These proteins confer specific properties to lipoprotein particles, as detailed later in this chapter. 

After its absorption into the intestinal mucosal cell, cholesterol, together with triglycerides, phospholipids, and a number of specific apoproteins, is assembled into a large lipoprotein called the chylomicron (see later section on lipoprotein metabolism, exogenous pathway). One apoprotein component known as apolipoprotein (apo) B-48 is vital to the formation of chylomicrons, and in people with a rare deficiency of apo B-48 synthesis, chylomicron formation, and consequently cholesterol and fat absorption, is severely impaired. Chylomicrons enter the lymphatics, which empty into the thoracic duct and eventually enter the systemic venous circulation at the junction of the left subclavian vein and left internal jugular vein. 

B-48 Chylomicrons Trace 264 Necessary for assembly and secretion of chylomicrons from the small intestine Intestine... 

Only two types of lipoproteins, VLDL and chylomicrons, are fully formed within cells by assembly in the ER, a process that requires the activity of microsomal transfer protein. The assembled particles move through the secretory pathway to the cell surface and are released by exocytosis—VLDL from liver cells and chylomicrons from intestinal epithelial cells (see Figure 18-10b). LDLs, IDLs (intermediate-density lipoproteins), and some HDLs are generated extracellularly in the bloodstream and on the surfaces of cells by the remodeling of secreted VLDLs and chylomicrons. There are four types of modifications ... 

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