Cholesterol ester excretion

In our laboratory, we have observed that pectin increased cholesterol ester excretion in rats fed a cholesterol-containing diet (26). An early report ( ] indicated that fecal excretion of endogenous cholesterol ester could be influenced by the type of fat. Polyunsaturated fat (com oil] as compared with saturated fat (lard] accelerated cholesterol ester, but not total cholesterol excretion (27). It was suggested that, under certain circumstances, cholesterol ester excretion was one of the major pathways of cholesterol catabolism and a process for lowering body cholesterol and might explain why corn oil lowers serum... 

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. 

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. 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

The only receptor-mediated uptake process regulated in macrophages involves suppression of )8-VLDL receptors. This suppression only occurs after extensive cholesterol ester accumulation and can be induced by either j8-VLDL or chemically modified LDL [13]. Lipoprotein uptake by all known receptor systems in macrophages causes a marked stimulation of ACAT activity which results in the massive accumulation of cholesteryl ester droplets in the cytoplasm [13]. Free cholesterol can be excreted from the macrophage if cholesterol-accepting Upoproteins such as HDL are present. The uncontrolled uptake and deposition of cholesteryl esters in macrophages is believed to be the key to formation of the foam cells which are associated with atherosclerosis. 

HDL is considered to be the good cholesterol, because it accepts free cholesterol from peripheral tissues, such as cells in the walls of blood vessels. This cholesterol is converted to cholesterol ester, part of which is transferred to VLDL by CETP, and returned to the liver by IDL and LDL. The remainder of the cholesterol is transferred directly as part of the HDL molecule to the liver. The liver reutilizes the cholesterol in the synthesis of VLDL, converts it to bile salts, or excretes it directly into the bile. HDL therefore tends to lower blood cholesterol levels. Lower blood cholesterol levels correlate with a lower rates of death of atherosclerosis. 

Dietary pectin affects lipid metabolism, especially that of cholesterol. One of the explanations proposed to explain an action of pectin on cholesterol metabolism is through its ability to bind bile acids and bile salts. However, pectin also has the property of forming a gel in water. This gel lowers the intestinal absorption of cholesterol and thereby decreases liver cholesterol. Recently, evidence has been obtained that the presence of pectin in a cholesterol diet increases the excretion of cholesterol esters. Results from the administration of cholesterol-4-l C in the diet showed that the presence of pectin slows gastric emptying and results in more labeled cholesterol as well as cholesterol esters in all segments of the gut. 

Fig< 1< CO-6 fatty adds in serum cholesterol esters and excretion of prostagiandin metabolites in urine depend- q ing on linoleic add supply after heavy injury... 

Scheme 113.1 Schematic overview of cholesterol metabolism and main proposed mechanisms of action of phytosterols. 1. The absorption of dietary and/or biliary cholesterol is reduced by competition with PS for incorporation into mixed micelles. 2. Esterification of free cholesterol in the enterocyte is reduced by competition with PS for ACAT-2 enzyme. 3. Upregulation of the heterodimer ABCG5/G8 by PS can increase intestinal and hepato-biliar secretion. 4. Upregulation of ABCAl by PS can increase the incorporation of sterols into nascent HDL. 5. Increased cholesterol excretion via TICE. 6. Although it is not directly mediated by PS, the lower levels of hepatic cholesterol can lead to a lower VLDL secretion and upregulation of LDL receptor, which improves the clearance of plasma cholesterol. Abbreviations FC free cholesterol, CE cholesterol esters, ACAT-2 Acyl-CoA cholesterol O-acyltransferase 2, CM chylomicron, CMR chylomicron remnant, TICE transintestinal cholesterol efflux, LDL low-density lipoprotein, IDL intermediate-density lipoprotein, HDL high-density lipoprotein...

HDL is produced in liver and other tissues. This lipoprotein fraction is especially enriched in protein and phospholipid, with very little tri-gylceride. The major protein components are apo Aj and An, with small amounts of apo Cn and E. HDL also carries a substantial portion of cholesterol, as much as 20% of the total blood cholesterol level. HDL functions to transport cholesterol from peripheral tissues to the liver. Cholesterol on the surface of cells or other lipoproteins is picked up by HDL and esterified via lecithin-cholesterol acyltransferase (LCAT) to cholesterol ester for transport in the lipid core of HDL. The acquisition of cholesterol appears to be mediated via apo Ai (Barbaras et aL, 1987). LCAT also appears to be activated by apo Aj present within HDL. Cholesterol delivered to the liver by HDL is thought to be excreted as bile acids. 

The role of linoleate in cholesterol deposition and transport is not entirely clear. Kelsey and Longenecker (1941) proved that 62% of the plasma cholesterol of cattle occurred in combination with linoleate. It is only natural to postulate that, in the absence of EFA, cholesterol is deposited in the liver, because there is insufficient linoleate available to transport it to other tissues for metabolism and excretion. However, it has been shown that, in such conditions, the increased cholesterol is deposited in the liver as an ester. The cholesterol esters in the liver of rats have been proved to consist almost entirely of those of saturated and oleic acids only approximately 10% of the cholesterol occurs in combination with linoleic acid, irrespective of whether or not the diet contains EFA (Achaya et al., 1954a). It would thus appear that Unoleic acid is of prime importance in the control of the distribution and deposition of cholesterol in the rat. Whether or not the same situation obtains in the case of man is a moot question. 

HDL also takes up free cholesterol from extrahepatic tissues and esterifres it using LCAT, an enzyme that is activated by the apoA-1 component of HDL. Cholesterol esters are then transferred to VLDL and LDL in exchange for TAG, or they are transported to the liver, where cholesterol is converted to hile acids or excreted. 

Contrary to LDL, high-density lipoproteins (HDL) prevent atherosclerosis, and therefore, their plasma levels inversely correlate with the risk of developing coronary artery disease. HDL antiatherogenic activity is apparently due to the removal of cholesterol from peripheral tissues and its transport to the liver for excretion. In addition, HDL acts as antioxidants, inhibiting copper- or endothelial cell-induced LDL oxidation [180], It was found that HDL lipids are oxidized easier than LDL lipids by peroxyl radicals [181]. HDL also protects LDL by the reduction of cholesteryl ester hydroperoxides to corresponding hydroperoxides. During this process, HDL specific methionine residues in apolipoproteins AI and All are oxidized [182]. 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

FIGURE 6.22 Shuttling of cholesterol from one type of cell to another. An HDL may pick up cholesterol from a macrophage, a white blood cell that phagocytizes debris in the bloodstream (e.g., dead red blood cells). A dead red blood cell contains cholesterol, since it contains a plasma membrane. (1) The macrophage can donate the cholesterol (that it has "eaten") to a passing HDL. (2) The cholesteryl ester that is formed is then transferred, in the circulation, to a VLDL. This transfer is catalyzed by an enzyme in the bloodstream called cholesteryl ester transfer protein (CETP). (3) Eventually, the cholesteryl ester can be delivered to the liver and excreted as a bile salt or (4) delivered to a cholesterol-needy cell. This ceU may be a premature red blood cell that is engaging in membrane synthesis and mitosis. 

Apolipoprotein A-I (ApoA-I) ApoA-I is the major protein component of HDL in plasma. The protein helps to clear cholesterol from arteries and promotes cholesterol efflux form tissues to the liver for excretion. It is a cofactor for lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of most plasma cholesteryl esters. 

Sucrose polyester - In normal volunteers, doses of 8-25 g/day of sucrose polyester, a liquid non-hydrolyzable unabsorbable long chain fatty acid ester of sucrose, lowered total and LDL-C without altering serum triglycerides or HDL-C. The material inhibited cholesterol absorption and increased the excretion of neutral sterols and bile acids. 

Catabolism of chylomicron remnants may be viewed as the second step in the processing of chylomicrons. After the loss of apo C-II and other C and A apoproteins, LPL no longer acts upon the remnants, and they leave the capillary surface. Chylomicron remnants are rapidly removed by uptake into liver parenchymal cells via receptor-mediated endocytosis. Apo E is important in this uptake process. The chylomicron receptors in liver are distinct from the B-E receptor that mediates uptake of LDL. The hepatic receptor for chylomicrons binds with apo E, but not apo B-48. Another receptor, known as the LDL receptor-related protein (LRP), may also function in chylomicron uptake. Chylomicron remnants are transported into the lysosomal compartment where acid lipases and proteases complete their degradation. In the liver, fatty acids so released are oxidized or are reconverted to triacylglycerol, which is stored or secreted as VLDL. The cholesterol may be used in membrane synthesis, stored as cholesteryl ester, or excreted in the bile unchanged or as bile acids. 

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