Lipoproteins liver uptake

VLDL Transports tr yceride from liver to tissues apoB-100 apoC-n apoE Secreted by Uver Activates lipoprotein lipase Uptake of remnants by liver... 

C-l II Chylomicrons, VLDL, HDL 8.75 Liver 12-15 Inhibitor of LPL, involved in lipoprotein remnant uptake... 

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

Kempen et al. [176] synthesized a water-soluble cho-lesteryl-containing trigalactoside, Tris-Gal-Chol (I), which when incorporated in lipoproteins allows the utilization of active receptors for galactose-terminated macromolecules as a trigger for the uptake of lipoproteins. The effect of increasing concentrations of Tris-Gal-Chol on the removal of LDL and HDL from serum and their quantitative recovery in the liver is shown in Fig. 13. These data show that lipoproteins containing Tris-Gal-Chol can be used as a liver-specific drug-carrier system. 

ApoC-I is expressed mainly in liver but also in lung, skin, testis, spleen, neural retina, and RPE. Its multiple functions include the activation of lecithin cholesterol acyltransferase (LCAT) and the inhibition, among others, of lipoprotein and hepatic lipases that hydrolyze triglycerides in particle cores. Notably, both LCAT and lipoprotein lipases are expressed in RPE and choroid (Li et al., 2006). Moreover ApoC-I has been shown to displace ApoE on the VLDL and LDL and thus hinder their binding and uptake via their corresponding receptors (Li et al., 2006). 

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. 

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 HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

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... 

The LDL receptor also binds to apoE and plays a significant role in the hepatic uptake of chylomicrons and VLDL remnants. However, if LDL receptors are unavailable (as, for example, in a mouse strain that lacks the gene for the LDL receptor), VLDL remnants and chylomicrons are still taken up by the liver even though LDL is not. This indicates the presence of a back-up system for receptor-mediated endocytosis of VLDL remnants and chylomicrons. One back-up receptor is lipoprotein receptor-related protein (LRP), which binds to apoE as well as to a number of other ligands. 

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... 

As mentioned in Chapter 21, there are several related receptors with similar structures. Two of them have a specificity for apolipoprotein E and can accept remnants of VLDL particles and chylomicrons.216 220 The LDL receptor-related protein is a longer-chain receptor.216 221 LDL particles, especially when present in excess or when they contain oxidized lipoproteins, may be taken up by endocytosis into macrophages with the aid of the quite different scavenger receptors.221 225 The uptake of oxidized lipoproteins by these receptors may be a major factor in promoting development of atherosclerosis (Box 22-B). On the other hand, scavenger receptor SR-B1, which is also present in liver cells, was recently identified as the receptor for HDL and essential to the "reverse cholesterol transport" that removes excess cholesterol for excretion in the bile.213/213a... 

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. 

The uneven but wide tissue distribution of most dietary carotenoids may indicate an active biological role for these compounds (see Chapter 20). The organs with the greatest number of low-density lipoprotein (LDL) receptors and the highest rates of lipoprotein uptake (adrenals, testes, and liver)... 

Grove RI, Mazzucco C, Allegretto N, et al. Macrophage-derived factors increase low-density lipoprotein uptake and receptor number in cultured human liver cells. J Lipid Res 1991 32 1889-1897. 

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. 

K. Fluiter and T. J. C. Van Berkel, Scavenger receptor B1 (SR- Bl) substrates inhibit the selective uptake of high-density-lipoprotein cholesteryl esters by rat parenchymal liver cells, Biochem. J. 326 515-519 (1997). 

VLDLs are synthesized in the liver and transport triacylglycerols, cholesterol and phospholipids to other tissues, where lipoprotein lipase hydrolyzes the triacylglycerols and releases the fatty acids for uptake. The VLDL remnants are transformed first to IDLs and then to LDLs as all of their apoproteins other than apoB-100 are removed and their cholesterol esterified. The LDLs bind to the LDL receptor protein on the surface of target cells and are internalized by receptor-mediated endocytosis. The cholesterol, which is released from the lipoproteins by the action of lysosomal lipases, is either incorporated into the cell membrane or re-esterified for storage. High levels of intracellular cholesterol decrease the synthesis of the LDL receptor, reducing the rate of uptake of cholesterol, and inhibit HMG CoA reductase, preventing the cellular synthesis of cholesterol. 

It is likely that the major site of uptake of apoE-containing remnants of the triglyceride-rich lipoproteins is the liver. As apoC is removed and the apoE apoC ratio rises, so the remnant lipoprotein becomes more amenable to hepatic uptake by specific receptors (S25, S28, W16, W17). VLDL remnants and IDL also experience apoE-mediated binding by apoB,E receptors in hepatic cell membrane preparations (H35, Mil). The smallest apoE-rich VLDL subfractions from normolipidemic human plasma compete with LDL for fibroblast (apoB-100,E) receptors in vitro (T10) and in cultured fibroblasts (F17, G2, 17). ... 

It is, of course, also possible that the esterified cholesterol formed in HDL may be removed from plasma by some process other than uptake of the whole HDL particle or LTP-I-mediated transfer to other lipoprotein particles, but this possibility has not been fully investigated. Some evidence that there may be other pathways than these for the removal from plasma of HDL esterified cholesterol comes from the studies of Class et al. (G5, G6), who showed that cholesteryl ether incorporated in rat HDL as a tracer for cholesteryl ester was taken up in vivo by the rat liver (and by other organs) fester than apoA-I tracer (see Section 4.1.2). These studies are complicated by the relatively high concentration of apoE in rat HDL (compared, for instance, to man) and the unknown effect of apoE on HDL cholesteryl ester metabolism in the rat. Further studies on the removal of esterified cholester-... 

G6. Glass, C., Pittman, R. C., Weinstein, D. B., and Steinberg, D., Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc. Natl. Acad. Sci. U.S.A. 80, 5435-5439 (1983). 

Ose, L., Ose, T., Norum, K. R., and Berg, T., Uptake and degradation of 125I-labelled high density lipoprotein in rat liver cell in vivo and in vitro. Biochim. Biophys. Acta 574, 521-536 (1979). 

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