Lipoproteins metabolic transformations

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...

Figure 5.6 General scheme of lipoprotein metabolism. Triacylglycerols and cholesterol are exported from the liver in VLDLs, containing apolipoprotein B-lOO they further acquire apo-C-I, II, III and apo-E from circulating HDL. Apo-C-II activates lipoprotein lipase to remove fatty acids from VLDLs. As triacylglycerols are removed, VLDLs transform to IDEs and finally LDLs. LDLs are the main vehicle for transfer of cholesterol to the tissues uptake of LDL occurs primarily in the liver through LDL-receptor-mediated endocytosis, which requires the presence of apo-B-100. HDLs are synthesised essentially devoid of cholesterol or triacylglycerol and provide a circulating source of apo-C-I, II and apo-E. HDLs gradually accumulate cholesteryl esters, eventually returning these to the liver, mediated by an apo-A-I receptor this is referred to as reverse cholesterol transport. ...

The principal functions of the lipoprotein classes are determined by their apolipoprotein (apo) and lipid components. The CM are synthesized in the intestines for the transport of dietary triacylglycerols to various tissues (Chapter 19). VLDL are synthesized in the liver for the export of endogenous triacylglycerols (Chapter 19), while LDL arise from the metabolic transformation of VLDL in circulation (Chapter 20). The function of LDL is to deliver CE to peripheral tissues and to the liver. HDL are synthesized and assembled in the liver and intestine or are formed from metabolic transformations of other lipoproteins in circulation, and from cellular lipids at the cell membranes (see Chapter 20). HDL remove excess cholesterol from cells and transport it to liver and steroidogenic tissues for metabolism and excretion. 

In the fasted state, the fatty acid composition of lipoprotein lipids reflects their biosynthetic origins and metabolic transformations in circulation (Table 2) [6]. 

Investigation of the conformational adaptability of apolipoproteins during assembly with lipids and during metabolic transformations of lipoproteins in circulation. Elucidation of the conformational changes at the atomic level will be a major challenge dependent on the success of high-resolution analysis of apolipoprotein and lipoprotein structures. 

Lipoprotein metabolism involves three distinct processes (Smith et al., 1978). Physical exchange and transfer processes transform the nascent forms of the lipoproteins, secreted from the intestine... 

Both intact carotenoids and their apolar metabolites (retinyl esters) are secreted into the lymphatic system associated with CMs. In the blood circulation, CM particles undergo lipolysis, catalyzed by a lipoprotein lipase, resulting in the formation of CM remnants that are quickly taken up by the liver. In the liver, the remnant-associated carotenoid can be either (1) metabolized into vitamin A and other metabolites, (2) stored, (3) secreted with the bile, or (4) repackaged and released with VLDL particles. In the bloodstream, VLDLs are transformed to LDLs, and then HDLs by delipidation and the carotenoids associated with the lipoprotein particles are finally distributed to extrahepatic tissues (Figure 3.2.2). Time-course studies focusing on carotenoid appearances in different lipoprotein fractions after ingestion showed that CM carotenoid levels peak early (4 to 8 hr) whereas LDL and HDL carotenoid levels reach peaks later (16 to 24 hr). 

The liver has a variety of functions in lipid metabolism (7.) uptake, oxidation and transformation of free fatty acids, (2.) synthesis of plasma lipoproteins, (3.) trans-... 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

Deficiency of mature lipoprotein fractions, be it the consequence of an abnormality of the apolipoprotein(s) or of a deficient synthesis, can have a significant clinical impact in some cases whereas in others it may go almost unnoticed. The study of hpoprotein deficiency syndromes has received considerable help from the recent advances in molecular cloning both of apohpoproteins and of major enzymes involved in lipid metabolism. This type of information has allowed the conclusion that hpoprotein deficiency syndromes are very often associated with well-characterized abnormalities in the processing and/or transformation of hpoproteins or apohpoproteins in the carriers. 

It can be seen then that the metabolic state of the cell is an important factor influencing surface membrane functions. Where viral transformation causes cancer-like properties, metabolic control at the nucleic acid level is likely, although viral-host interactions seem more complex than first theorized (Altman and Katz, 1976). Receptors for enteroviruses have been reported and shown to be specific for various viral strains. Susceptibility to viral infection is correlated with the presence of receptor sites on intracellular membranes as well as on the cell surface. Chemically, virus receptors solubilized from plasma membranes have been determined to be lipoproteins, with the protein moiety being most important in determining receptor activity (McLaren et al., 1968). A review of cell membrane receptors for viruses, antigens and... 

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