Chylomicron remnants liver uptake

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... 

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-lOO, E) receptor and the LRP (LDL receptor-related protein)... 

The rationale for this type of contrast agent is to use the endogenous metabolic pathway of lipid metabolism in the liver for the transport of iodinated substances. Chylomicron remnants are naturally occurring lipoproteins in the blood that are responsible for the transport of lipids into the liver. Three different mechanisms for this transport are discussed direct uptake by the low-density lipoprotein receptor transport to the low-density lipoprotein receptor-related protein (LRP) mediated by heparan sulfate proteoglycan (HSPG) or direct HSPG-LRP uptake and direct HSPG uptake. One of the prerequisites for particles to be transported by these mechanisms is a mean diameter of less than 100-300 run. 

Lee SJ, Grosskopf I, Choi SY, Cooper AD (2004) Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins , E2 (Argl58->Cys), and E3-Leiden. J Lipid Res 45 2199-2210... 

Vitamin E, like neutral lipids, requires apoB lipoproteins at every stage of its transport (Fig. 27-2). Dietary vitamin E becomes emulsified in micelles produced during the digestive phase of lipid absorption and permeates the intestinal epithelium, similar to fatty acids and cholesterol. Uptake of vitamin E by enterocytes appears to be concentration dependent. Within intestinal cells, vitamin E is packaged into chylomicrons and secreted into lymph. During blood circulation of chylomicrons, some vitamin E may be released to the tissues as a consequence of partial lipolysis of these particles by endothelial cell-anchored lipoprotein lipase. The rest remains associated with chylomicron remnants. Remnant particles are mainly endocy-tosed by the liver and degraded, resulting in the release of fat-soluble vitamins. 

In intestinal mucosal cells, all vitamers of vitamin E cue incorporated into chylomicrons, and tissues take up some vitamin E from chylomicrons. Most, however, goes to the liver in chylomicron remnants, a -Tocopherol, which binds to the liver a-tocopherol transfer protein, is then exported in very low-density lipoprotein (VLDL) and is available for tissue uptake (Traber and Aral, 1999 Stocker and Azzi, 2000). Later, it appears in low-density Upoprotein (LDL) and high-density lipoprotein, as a result of metabolism of VLDL in the circulation. The other vitamers, which do not bind well to the a-tocopherol transfer protein, are not incorporated into VLDL, but are metabolized in the Uver and excreted. This explains thelower biological potency of the othervitcimers,despitesimilar, or higher, in vitro antioxidant activity. 

The uptake of chylomicron remnants by the liver results in delivery of retinol to this organ for storage as a lipid ester within lipocytes. 

Vitamin E is absorbed from the intestines packaged in chylomicrons. It is delivered to the tissues via chylomicron transport and then to the liver through chylomicron remnant uptake. The liver can export vitamin E in VLDLs. 

How do VLDLs remain in the bloodstream long enough to donate their lipids to needy ceils before being taken up by the liver The apo C of the VLDLs appears to prevent their uptake by the liver by covering or obscuring apo E. (The apo C of chylomicrorLS also prevents their uptake before they are converted to chylomicron remnants.) However, with continued residence in the circulation, the apo C ev en-tually is transferred to HDLs. This loss of apo C exposes both apo E and apo B to the environment. Each VI.DL remnant molecule contains several molecules of apo E, which, when exposed, bind avidly to LDL receptors. The VLDL remnant then is taken up by the liver within minutes or hours. 

The following case history concerns apo H. The absence of apo E prevents efficient uptake of chylomicron remnants and IDLs by the liver thus, the concentre lions of these particles and their constituent TGs and choJcsteryl esters can increase dramatically in the plasma. The following comment concerns LDLs, and not the remnants of IDI. The uptake of LDLs is not affected by the disease, because their uptake is mediated by interactions with the apo B receptor (LDL receptor). 

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. 

Sources of HDL. HDL is derived from de novo production in the intestinal mucosa and liver, as well as from breakdown of chylomicrons and possibly VLDL. Nascent HDL is discoidal when first formed and becomes spherical in plasma as the formation and storage of cholesteryl ester in its cores (via LCAT) lowers the surface-to-volume ratio. Nascent chylomicrons pick up apo C from plasma HDL, which serves to hinder chylomicron uptake by the liver. After losing a substantial portion of their triacylglycerols to peripheral tissues via lipoprotein lipase, chylomicrons recycle most of their apo C back to HDL, and then gain apo E, which mediates their hepatic uptake as chylomicron remnants. 

C-III, and phospholipids are transferred to EfDL. Apolipoproteins E and C-II are transferred to chylomicrons from EfDL and evenmally back through these metabolic events. Hepatic VLDL synthesis is regulated in part by diet and hormones and is inhibited by uptake of chylomicron remnants in the liver. VLDL is secreted from the Ever and serially converted via LPL to intermediate-density hpoprotein (IDL) and finally to LDL. VLDL receptors are found in adipose tissue and muscle and bear close homology to the structure of LDL receptors. 

C-l Chylomicrons, VLDL, HDL 7 6.6 Cofactor with LCAT, may inhibit hepatic uptake of chylomicron and VLDL remnants Liver... 

Ann Jeina was treated with a statin (pravastatin) and cholestyramine, a bile acid sequestrant. With the introduction of the cholesterol absorption blocker ezetimibe, the use of cholestyramine with its high level of gastrointestinal side effects may decline. Ezetimibe reduces the percentage of absorption of free cholesterol present in the lumen of the gut and hence the amount of cholesterol available to the enteroc5de to package into chylomicrons. This, in turn, reduces the amount of cholesterol returning to the liver in chylomicron remnants. The net result is a reduction in the cholesterol pool in hepatocytes. The latter induces the synthesis of an increased number of LDL receptors by the hver cells. As a consequence, the capacity of the liver to increase hepatic uptake of LDL from the circulation leads to a decrease in serum LDL levels. 

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