Lipoproteins metabolic pathways

Figure 26-18 Exogenous lipoprotein metabolism pathway. TG, Triglyceride CE, cholesterol ester FC, free cholesterol Ft, phospholipids HDL, hIgh-density lipoproteins FA, fatty acid LPL, lipoprotein lipase 6, apolipoprotein B-48 A, apolipoprotein A-i C, apolipoprotein C-ll , apolipoprotein E. (From Rifai N. Lipoproteins and apolipoproteins Composition, metabolism, and association with coronary heart disease. Arch Pathol Lab Med 1986 10 694-701. Copyright 1986, American Medical Association.)...

Finally, increasing our knowledge about modulators of the activity of the LDL receptor family (such as ARH [32] and PCSK9 [8], Section 2.5) will be important for the characterization of modifier genes of lipoprotein metabolic pathways in the general population. 

Lipoprotein Metabolism. Figure 1 Exogenous pathway of lipoprotein metabolism. 

FIGURE 3.2.2 Metabolic pathways of carotenoids such as p-carotene. CM = chylomicrons. VLDL = very low-density lipoproteins. LDL = low-density lipoproteins. HDL = high-density lipoproteins. BCO = p-carotene 15,15 -oxygenase. BCO2 = p-carotene 9, 10 -oxygenase. LPL = lipoprotein lipase. RBP = retinol binding protein. SR-BI = scavenger receptor class B, type I. 

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 LDL particles contain one apoB-100 as the structural protein and are the major cholesterol-transporting lipoproteins in human blood. Clearance of LDL from blood is mediated by the interaction of apoB-100 with the LDLR. Genetic defects either in the receptor binding region of apoB-100 or in the LDLR lead to decreased clearance of LDL and hence to their accumulation in the blood. The major metabolic pathways of the lipoprotein metabolism are shown in Fig. 5.2.1. 

R.W. Mahley and Z.S. Ji, Remnant lipoprotein metabolism key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E, J. Lipid Res. 40 (1999) 1-16. 

An alternative metabolic pathway is available to a VLDL. in this process, the particle loses its apo E as it matures to an IDL. Without apo E, the particle is not efficiently taken up by the liver but continues to circulate in the bkKdstream. Continued removal of TGs from an IDL produces a lipoprotein particle called an LDL that is enriched in cholesteryl esters. After conversion to an LDL, only a single apo B molecule remains on the surface of the particle. This protein binds only relatively weakly to an LDL receptor. Consequently, LDLs have residence times in the circulation of about 3 days. Eventually, LDLs are taken up by various tissues. The receptor that binds an LDL, called an LDL receptor, is similar, or perhaps identical, to the receptors that bind circulating IDLs and mediate their entry into hepatocytes. 

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. 

The pathways of lipoprotein metabolism are complex. They include exogenous and endogenous pathways based on whether they carry lipids of dietary or hepatic origin (Figures 26-18 and 26-19) and other pathways such as the... 

Historically, lipoprotein phenotypes reflecting lipoprotein metabolic disorders were classified according to Fredrickson and co-workers. However, these disorders are more rationally approached based on the four metabolic pathways discussed previously (see Figures 26-18 through 26-21). Defects in these pathways, leading to hyperlipidemia, may be related to (1) increased production of lipoproteins, (2) abnormal intravascular processing (e.g., enzymatic... 

Fig. 1. Simplified schematic summary of the essential pathways for receptor-mediated human lipoprotein metabolism. The liver is the crossing point between the exogenous pathway (left-hand side), which deals with dietary lipids, and the endogenous pathway (right-hand side) that starts with the hepatic synthesis of VLDL. The endogenous metabolic branch starts with the production of chylomicrons (CM) in the intestine, which are converted to chylomicron remnants (CMR). Very-low-density lipoprotein particles (VLDL) are lipolyzed to LDL particles, which bind to the LDL receptor. IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LCAT, lecithinxholesterol acyltransferase CETP, cholesteryl ester transfer protein A, LDL receptor-related protein (LRPl) and W, LDL receptor. Lipolysis denotes lipoprotein lipase-catalyzed triacylglycerol lipolysis in the capillary bed.

Emulsions intended for total parenteral nutrition (TPN) are formulated using vegetable or neutral oils as dispersed phase and phospholipids as emulsifier with the objective that they are not recognized as foreign by the body. They can be considered as being artificial chylomicrons and enter the fat metabolism pathway through the adsorption of apolipoproteins and the subsequent action of lipoprotein lipase. 

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