Cholesterol lipoprotein distribution

Cholesterol is biosynthesized in the liver trans ported throughout the body to be used in a va riety of ways and returned to the liver where it serves as the biosynthetic precursor to other steroids But cholesterol is a lipid and isn t soluble in water How can it move through the blood if it doesn t dis solve in if The answer is that it doesn t dissolve but IS instead carried through the blood and tissues as part of a lipoprotein (lipid + protein = lipoprotein) The proteins that carry cholesterol from the liver are called low density lipoproteins or LDLs those that return it to the liver are the high-density lipoproteins or HDLs If too much cholesterol is being transported by LDL or too little by HDL the extra cholesterol builds up on the walls of the arteries caus mg atherosclerosis A thorough physical examination nowadays measures not only total cholesterol con centration but also the distribution between LDL and HDL cholesterol An elevated level of LDL cholesterol IS a risk factor for heart disease LDL cholesterol is bad cholesterol HDLs on the other hand remove excess cholesterol and are protective HDL cholesterol IS good cholesterol... 

Cholesterol (Figure 14-17) is widely distributed in all cells of the body but particularly in nervous tissue. It is a major constituent of the plasma membrane and of plasma lipoproteins. It is often found as cholesteryl ester, where the hydroxyl group on position 3 is esteri-fied with a long-chain fatty acid. It occurs in animals but not in plants. 

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

HDL cholesterol picked up in the periphery can be distributed to other lipoprotein particles such as VLDL remnants (IDL), converting them to LDL. The cholesterol ester transfer protein facilitates this transfer, shotvn in Figure 1-15-6. 

Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins. Certain lipoproteins contain very high-molecular-weight proteins that exist in two forms B-48, formed in the intestine and found in chylomicrons and their remnants and B-lOO, synthesized in liver and found in VLDL, VLDL remnants(IDL),LDL (formed from VLDL), and Lp(a) lipoproteins. HDL consist of at least 15 discrete molecular species. All species contain apolipoprotein A-I (apoA-I). Fifty-three other proteins are known to be distributed variously among the HDL species. 

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...

Similarly, apolipoprotein E expression increases in neurotoxicity mediated by KA (Table 6.3) (Boschert et al., 1999). Apolipoprotein E is a major lipoprotein in the brain. It is involved in the transport, distribution, and other aspects of cholesterol homeostasis. Apolipoprotein E also plays a dominant role in the mobilization and redistribution of brain lipids in repair, growth, and maintenance of nerve cells (Mahley, 1988). The secretion of apolipoproteins E and D may be differentially regulated in cultured astrocytes. In cell culture systems this depends upon the extracellular lipid milieu (Patel et al., 1995). During neurotoxicity mediated by KA, apolipoprotein E levels increase moderately in astrocytes and apolipoprotein E mRNA increases very strongly in clusters of CA1 and CA3 pyramidal neurons. Based on hybridization in situ and immunohistochemical studies, expression of apolipoprotein E in neurons may be a part of a rescue program to counteract neurodegeneration mediated by KA (Boschert et al., 1999). 

The major function of LTP-I in human plasma may be to distribute es-terified cholesterol from the HDL fraction, where cholesterol is esterified, to other lipoprotein fractions. LCAT activity is responsible for the production of some 50-100 nmol esterified cholesterol per milliliter of plasma per hour (Gil). The concentration of esterified cholesterol in human HDL is about 1000 nmol/ml of plasma. Only 0.5-1.0% of HDL apoprotein is removed from plasma per hour (B41), probably mainly in intact HDL particles. If so, then the uptake of HDL particles can account for the removal from plasma of only about 10-20% of the esterified cholesterol formed in HDL in the LCAT reaction. 

In this way, it is possible that in man LTP-I distributes a large proportion of the esterified cholesterol formed to VLDL and thus to LDL. If so, LTP-I might be considered atherogenic, in that its activity is responsible for much of the esterified cholesterol in the major atherogenic lipoprotein, LDL. By contrast, those species with low levels of plasma LTP-I activity, such as the dog, rat, pig, cow, and sheep (HI) have low plasma LDL esterified cholesterol concentrations (C2) and tend to be resistant to the development of atherosclerosis. 

When infants were fed the same amount of palmitic acid, significantly lower values of high-density lipoprotein-cholesterol and of apolipoprotein A and significantly higher levels of apoB were found in infants when the same amount of palmitic acid was fed in TAGs in the i 2-position than in the i l(3)-position (69). This illustrates that lipoprotein metabolism can be affected by fatty acid distribution in TAGs. 

The normal function of lipoproteins is to distribute and recycle cholesterol. The pathways of lipid metabolism and transport and their primary (inherited) disorders appear in Figure 25.1 and can be summarised thus ... 

In liver cirrhosis, there are several changes reduction in LCAT (with cholesterol ester fall ), HDL and LDL as well as in VLDL, with a corresponding change in their distribution pattern occurrence of hypertriglycerid-aemia and atypical lipoproteins reduction in phospholipid synthesis (28), possibly with greatly impaired structure and function of the biomembranes. Hepatic extraction of bile acids is reduced with the result that they reach the peripheral circulation - even in the early stages of cirrhosis - and give rise to increased serum values. Bile acids have cholestatic and cytotoxic effects. When bile acid metabolism is markedly compromised, enteral absorption of fat-soluble vitamins is impeded, so that A, D, E and K hypovitaminoses may be observed. 

Vitamin K is absorbed from the gut with the aid of bile salts. The vitamin is not esterified to a fatty acid during absorption, as is the case with cholesterol and retinol. Vitamin E is transported to the bloodstream in chyJomicrons and distributed to the various tissues via the lipoproteins. 

The lipids of the diet include TGs, phospholipids, cholesteryl esters, cholesterol, and the fat-soluble vitamins. These nutrients require special types of biochemical machinery to facilitate their assimilation and distribution within the body. The biochemical apparatus used includes bile salts, apolipoproteins, serum albumin, and vitamin-binding proteins. Apolipoproteins are the primary subject of this section. The term apolipoprotein is used when referring only to the protein, whereas the term lipoprotein refers to the complex of apolipoprotein and lipid. 

An additional feature of cholesterol/fat-fed animal models is the accumulation of HDL-with apoE. In several species, including dogs (Mahley el ai, 1974 Mahley and Weisgraber, 1983), rats (Mahley and Holcombe, 1977 Weisgraber and Mahley, 1983), pigs (Mahley et ai, 1975), and mice (de Silva et ai, 1992), the HDL-with apoE is a prominent lipoprotein class that extends into the lower density ranges overlapping in its density distribution with LDLs. The HDL-with apoE in these spe-... 

Chylomicrons are synthesized in the intestine and transport dietary triglycerides and cholesterol. While circulating, the core triglycerides in these particles are hydrolyzed by lipoprotein lipase, which results in the production of a cholesterol-enriched remnant particle. When synthesized and initially released by the intestine, chylomicrons contain essentially no apoE, but as they circulate and are processed to remnants, the particles acquire apoE from other lipoprotein classes. This results in a shift of the distribution of apoE in plasma to the triglyceride-rich remnants in the absorptive state (Blum, 1982). 

Fat Metabolism The liver also plays a central role in synthesis, oxidation, storage, and distribution of lipids. It not only aids in the absorption of fats through the action of the bile salts, but also (1) both synthesizes and oxidizes fatty acids, cholesterol, triacylglycerols, and phospholipids (the major components of cell membranes) (2) synthesizes most of the plasma lipoproteins and (3) converts carbohydrates and proteins into fat. 

At birth, the typical plasma cholesterol concentration is about 66mg/dL, equally distributed among LDL and HDL with a very small amount in VLDL. Triglyceride concentration is only about 36mg/dL. Cord blood apo A-I, apo B-lOO, and Lp(a) showed mean concentrations of about 80, 33, and 4mg/dL, respectively. Lipid, lipoprotein cholesterol, and apoitpoprotein concentrations rise sharply during the first few months of life, with LDL becoming the major... 

Generalized structure of a lipoprotein molecule showing the distribution of polar components in an outer shell composed of free cholesterol, phospholipids, and amphipathic proteins and in an inner core composed of neutral triacylglycerols and cholesteryl esters. Phospholipids are oriented with polar head groups toward the aqueous environment and hydrophobic tails toward the neutral core, analogous to their positioning in the outer leaflet of the typical cell membrane. 

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