Chylomicron catabolism

As the lipoproteins are depleted of triacylglycerol, the particles become smaller. Some of the surface molecules (apoproteins, phospholipids) are transferred to HDL. In the rat, remnants that result from chylomicron catabolism are removed by the liver. The uptake of remnant VLDL also occurs, but much of the triacylglycerol is further degraded by lipoprotein lipase to give the intermediate-density lipoprotein (IDL). This particle is converted into LDL via the action of lipoprotein lipase and enriched in cholesteryl ester via transfer from HDL by the cholesteryl ester transfer protein. The half-life for clearance of chylomicrons from plasma of humans is 4-5 min. Patients with the inherited disease, lipoprotein lipase deficiency, clear chylomicrons from the plasma very slowly. When on a normal diet, the blood from these patients looks like tomato soup. A very-low-fat diet greatly relieves this problem. 

Deficient or defective apo C-II, the required activator for LPL, reduces the activity of this enzyme, impairs chylomicron catabolism, and increases plasma triglycerides (500 to 10,000 mg/dL). Those affected by this disorder have less than 10% of the normal concentration of apo C-II, the minimum amount necessary for normal LPL activity. Total cholesterol tends to vary considerably (150 to 890mg/dL) in these patients, but HDL and LDL cholesterol concentrations are below the 5th percentile. Furthermore, plasma apo A-I, A-II, and B-lOO concentrations are decreased, whereas apo C III and E concentrations are increased. 

Intestinal absorption of vitamin E is dependent upon normal processes of fat absorption. Specifically, both biliary and pancreatic secretions are necessary for solubilization of vitamin E in mixed micelles containing bile acids, fatty acids, and monoglycerides (Figure 3). a-Tocopheryl acetates (or other esters) from vitamin E supplements are hydrolyzed by pancreatic esterases to a-tocopherol prior to absorption. Following micellar uptake by entero-cytes, vitamin E is incorporated into chylomicrons and secreted into the lymph. Once in the circulation, chylomicron triglycerides are hydrolyzed by lipoprotein lipase. During chylomicron catabolism in the... 

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 VERY LOW DENSITY LIPOPROTEINS ARE RAPIDLY CATABOLIZED... 

The clearance of labeled chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while about 20% goes to the liver. However, the liver does not metabolize native chylomicrons or VLDL significantly thus, the fatty acids in the liver must be secondary to their metabolism in extrahepatic tissues. 

High-density lipoproteins are formed in the liver and intestines as a result of catabolism of chylomicrons and very low-density lipoproteins, and in comparison with other lipoproteins, they contain considerably more cholesterol esters with unsaturated fatty acids, as well as phospholipids and specific proteins. 

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,... 

Decreased catabolism of chylomicrons and VLDL has been demonstrated in nephrotic syndrome (D4). The fractional catabolic rate of apoliprotein B depends on the presence of hypertriglyceridemia The fractional catabolic rate of... 

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

Human lipoproteins exist in several sizes and densities with differing lipid to protein ratios. These various lipoproteins have different origins in the body, different destinations and different functions (10). Thus, chylomicrons are extremely large low density particles formed in the intestine and designed to deliver dietary fat to adipose tissue. Very low density lipoproteins (VLDL), on the other hand, are smaller, more dense particles designed to deliver lipids from the liver to adipose and other tissues. Low density lipoproteins (LDL), formed from VLDL or produced in the liver or intestine deliver cholesterol to peripheral tissue, while high density lipoproteins (HDL) function to return cholesterol from peripheral tissues to the liver for catabolism. There is a complex exchange of lipids and apoproteins between the lipoprotein classes. 

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis. ApoE, the major apolipoprotein of the chylomicron in the brain, binds to a specific receptor and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants (Mahley et al., 1999). In the brain, lipidated apoE binds aggregated in a isoform-speciflc manner, apoE4 being much more effective than the other forms,... 

This disorder is characterized by marked hyperchylomi-cronemia and a corresponding hypertriglyceridemia (triglyceride as high as 10,000 mg/dL). As discussed previously, LPL is essential for the hydrolysis of triglyceride and the conversion of chylomicrons to chylomicron remnants. The massive accumulation of chylomicrons in the circulation indicates the inability to catabolize dietary fat. The concentration of VXDL cholesterol is usually normal and the concentrations of HDL cholesterol and LDL cholesterol are low (type I pattern). Furthermore, the concentration of apo C-II, the activator of LPL, is normal. 

Intermediate-Density (Remnant) Lipoproteins Remnant lipoproteins include the lipolytic products of catabolism of the triglyceride-rich lipoproteins, VLDL and chylomicrons, occurring in the VLDL and LDL ranges. A traditionally defined fraction at the lighter end of the LDL density range, the IDL portion comprises the 1.006 to 1.019 g/mL fraction, which is obtained by sequential ultracentrifugation for quantitation, generally in terms of cholesterol content. 

Catabolism of chylomicron remnants may be viewed as the second step in the processing of chylomicrons. After the loss of apo C-II and other C and A apoproteins, LPL no longer acts upon the remnants, and they leave the capillary surface. Chylomicron remnants are rapidly removed by uptake into liver parenchymal cells via receptor-mediated endocytosis. Apo E is important in this uptake process. The chylomicron receptors in liver are distinct from the B-E receptor that mediates uptake of LDL. The hepatic receptor for chylomicrons binds with apo E, but not apo B-48. Another receptor, known as the LDL receptor-related protein (LRP), may also function in chylomicron uptake. Chylomicron remnants are transported into the lysosomal compartment where acid lipases and proteases complete their degradation. In the liver, fatty acids so released are oxidized or are reconverted to triacylglycerol, which is stored or secreted as VLDL. The cholesterol may be used in membrane synthesis, stored as cholesteryl ester, or excreted in the bile unchanged or as bile acids. 

Chylomicrons, large triglyceride-rich particles containing apolipoprotein B-48, B-lOO, and E, are formed from dietary fat solubilized by bile salts in intestinal mucosal cells (Fig. 21-2). Chylomicrons normally are not present in the plasma after a fast of 12 to 14 hours and are catabolized by lipoprotein lipase (LPL), which is activated by apolipoprotein C-II, in the vascular endothelium and hepatic lipase to form chylomicron remnants. The remnants that contain apolipoprotein E (see Fig. 21-2) are taken up by the remnant receptor, which may be an LDL-receptor-related protein, in the liver. Free cholesterol is liberated intracellularly after attachment to the remnant receptor. Chylomicrons also function to deliver dietary triglyceride to skeletal muscle and adipose tissue. During the catabolism of nascent chylomicrons to remnants, triglyceride is converted to free fatty acids and apolipoproteins A-I, A-II, A-IV (free in plasma), C-I, C-II, and... 

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