Lipoprotein uptake intestinal

In contrast to the extensive literature on the regulation of intestinal cholesterol synthesis, only a few studies are available on regulation of lipoprotein uptake in this organ. Notably, recent studies have compared the effect of various interventions such as the feeding of cholesterol, cholestyramine, surfomer, and com oil on both rates of cholesterol synthesis and LDL transport in the rat intestine in vivo, as shown in Fig. 9. While these various manipulations all alter rates of cholesterol synthesis, there is no consistent effect upon LDL uptake at any location in the mucosa, with the possible exception of a slight increase in the jejunum after feeding... 

Cholesterol-rich lipoprotein particles that carry dietary lipids absorbed in the intestine and deliver them to the liver for uptake. 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

The protein moieties of lipoproteins are recognized by receptors on cell surfaces. In lipid uptake from the intestine, chylomicrons, which contain apolipoprotein C-II (apoC-ID, move from the intestinal mucosa into the lymphatic system, and then enter the blood, which carries them to muscle and adipose tissue (Fig. 17-1, step... 

Liver and some intestinal cells export cholesterol into the bloodstream, together with triacylglycerols and phospholipids in the form of VLDL particles, for uptake by other tissues (see Fig. 21-1). Cholesteryl esters are formed in the ER by lecithin cholesterol acyltransferase (LCAT), an enzyme that transfers the central acyl group from phosphatidylcholine to the hydroxyl group of cholesterol.191 1913 This enzyme is also secreted by the liver and acts on free cholesterol in lipoproteins.192 Tissue acyltransferases also form cholesteryl esters from fatty acyl-CoAs.192a... 

The potential for orally administered drugs to enter the intestinal lymphatics is therefore defined by their selectivity for uptake into the intestinal lymphatics as opposed to the blood capillaries in the subepithelial space. Because selectivity for the lymphatics is primarily defined by size, it is apparent that only macromolecules or colloids will be preferentially absorbed into the intestinal lymphatics. However, the intestine provides a significant barrier to the absorption of both macromolecules and intact colloids, and the most prevalent mechanism for drug delivery to the intestinal lymph is by means of secondary drug association with intestinal lipoproteins [110]. The size of the drug-lipoprotein complex subsequently dictates absorption into the lymphatic vessels. 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

The main precursors of plasma HDL are most likely disk-shaped bilayers composed of PL and protein and secreted by the liver and intestine. HDL are also derived from the surplus surface material removed from TG-rich lipoproteins during lipolysis. HDL are involved in the net transfer of cholesterol from peripheral tissues to the liver, where it can be eliminated or recirculated. This process is initiated by the uptake of FC from cell membranes into the HDL. The nature of this uptake is not known but may involve binding of HDL to the membrane. 

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. 

High density lipoproteins (HDL2.3) are formed in the liver and small intestine. A minor proportion of the HDL appears to derive from triglyceride-rich lipoproteins in the plasma. HDL have a particle size of 5-15 nm and appear initially as disk-shaped bodies which, after uptake of lipids and lipoproteins, develop in the blood to spherically shaped molecules. They comprise ca. 50% hpids and 45-55% proteins. Their density is <1.21 g/ml. They are designated... 

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. 

Fig. I. Overall scheme for cholesterol balance across the intestinal epithelial cell. After digestion, lipids in the intestinal lumen combine with bile acids to form mixed micelles (MM) that promote uptake into the intestinal epithelial cell. Within the intestinal cell, triglyceride and cholesterol, along with specific apoproteins, are synthesized into the chylomicron (CM) which, ultimately, delivers much of the triglyceride to peripheral organs and most of the cholesterol to the liver. Also shown in this diagram are the 3 major sources for epithelial cell cholesterol including (1) uptake from the lumen, (2) synthesis from acetyl-CoA and (3) uptake of low-density lipoproteins (LDL) by both receptor-dependent and receptor-indqjendent mechanisms.

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