Cholesterol in intestine

Early work using the lymph fistula rat demonstrated that the amount of cholesterol appearing in intestinal lymph is directly proportional to the amount of dietary cholesterol present in the intestinal lumen [102]. Although less complete data are available in other species, this relationship also appears to be true in rabbit [103] and man [104]. Thus, in the post-absorptive state, after the intake of a diet containing substantial amounts of sterol, most cholesterol in intestinal lymph is probably derived from the diet [98]. 

Fig. 12. Appearance of newly synthesized cholesterol in mesenteric lymph of the rat. The experimental animals had indwelling lymph fistulae and were infused intraintestinally with a glucose-amino acid-electrolyte solution. One group of these animals was also administered intravenously chylomicrons containing lOS mg of cholesterol, while another group was infused intraduodenally with com oil. 24 h after the initial surgery, each animal was administered [ H]water intravenously and the secretion of labeled cholesterol in intestinal lymph was followed for 18 h. The amount of [ HJwater incorporated into cholesterol was used to calculate the amount of newly synthesized cholesterol present in lymph. These values are expressed as the nmoles of newly synthesized cholesterol secreted into the lymph each hour. The data points represent means +1 S.E.M.

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. 

Inhibitors of acyl CoA-cholesterol acyltransferase (ACAT) are currently being Investigated as cholesterol-lowering or antiatherosclerotic agents. In addition to its role in foam cell formation, ACAT also is required for esterification of cholesterol in intestinal mucosal cells and for synthesis of cholesterol esters in hepatic VLDL formation. Thus, ACAT inhibitors have the potential of providing three beneficial effects in patients with hypercholesterolemia decreased cholesterol absorption, decreased hepatic VLDL synthesis, and decreased foam cell formation. Initial successes at inhibiting ACAT were dampened by the discovery of accompanying adrenal toxicity. Subsequent structural modifications have lead to the development of... 

Enzymatic Conversion of Cholesterol. A decrease of cholesterol in meat products in the future may be possible through the conversion of cholesterol [57-88-5] to coprosterol [560-68-9] which is not absorbed readily in the intestine. Cholesterol reductase can be isolated from alfalfa leaves and cucumber leaves (53). Treatment of meat animals might involve an injection of this ensyme immediately prior to slaughter, allowing for the conversion of a portion of the membrane-bound cholesterol into coprostanol. 

Bde salts, cholesterol, phosphoHpids, and other minor components are secreted by the Hver. Bile salts serve three significant physiological functions. The hydrophilic carboxylate group, which is attached via an alkyl chain to the hydrophobic steroid skeleton, allows the bile salts to form water-soluble micelles with cholesterol and phosphoHpids in the bile. These micelles assist in the solvation of cholesterol. By solvating cholesterol, bile salts contribute to the homeostatic regulation of the amount of cholesterol in the whole body. Bile salts are also necessary for the intestinal absorption of dietary fats and fat-soluble vitamins (24—26). 

Saponins. Although the hypocholesterolemic activity of saponins has been known since the 1950s, thek low potency and difficult purification sparked Htde interest in natural saponins as hypolipidemic agents. Synthetic steroids (292, 293) that are structurally related to saponins have been shown to lower plasma cholesterol in a variety of different species (252). Steroid (292) is designated CP-88,818 [99759-19-0]. The hypocholesterolemic agent CP-148,623 [150332-35-7] (293) is not absorbed into the systemic ckculation and does not inhibit enzymes involved in cholesterol synthesis, release, or uptake. Rather, (293) specifically inhibits cholesterol absorption into the intestinal mucosa (253). As of late 1996, CP-148,623 is in clinical trials as an agent that lowers blood concentrations of cholesterol (254). 

HDL and VLDL are assembled primarily in the endoplasmic reticulum of the liver (with smaller amounts produced in the intestine), whereas chylomicrons form in the intestine. LDL is not synthesized directly, but is made from VLDL. LDL appears to be the major circulatory complex for cholesterol and cholesterol esters. The primary task of chylomicrons is to transport triacylglycerols. Despite all this, it is extremely important to note that each of these lipoprotein classes contains some of each type of lipid. The relative amounts of HDL and LDL are important in the disposition of cholesterol in the body and in the development of arterial plaques (Figure 25.36). The structures of the various... 

IKEDA I, IMASATO Y, SASAKI E, NAKAYAMA M, NAGAO H, TAKEO T, YAYABE F, SUGANO M (1992) Tea catechins decrease micellar solubility and intestinal absorption of cholesterol in rats. Biochim Biophys Acta. 1127 141-6. 

Pectin, the substance that makes jellies and jams so jelly-like, can help lower blood cholesterol levels by forcing the body to make more bile acids. Pectin is a type of fiber, and like most fiber, pectin cannot be digested by the human body. Instead, the fiber moves slowly through the small intestines. When pectin encounters sugar and acid, its molecules trap water within its long chains, turning into a gel-like mass. This gel traps and eventually eliminates bile acids from the gut. When this happens, the body must make more bile acids, reducing the amount of cholesterol in the blood. 

S Chapelle, M GiUes-BaiUien. Phospholipids and cholesterol in brush border and basolateral membranes from rat intestinal mucosa. Biochim Biophys Acta 753 269-271, 1983. 

Hauser, H. et al. (1998). Identification of a receptor mediating absorption of dietary cholesterol in the intestine. Biochemistry 37(51) 17843-17850. 

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. 

In the studies discussed, wheat bran, cellulose, and psyllium fiber feeding resulted in increased fecal fat losses and in lowered blood serum cholesterol and triglyceride levels (14,15,32,41) as well as increased fecal losses of calcium. Possible involvement of dietary fat with high or low dietary fiber intake has not been extensively investigated. However, that calcium is involved in intestinal fat absorption is generally accepted (42-45). 

Ezetrol contains ezetimibe, which selectively inhibits absorption of cholesterol in the intestine. It is used as monotherapy or in combination with other drug therapy as an adjunct to lifestyle measures in patients with hypercholesterolaemia. 

A and B are in cis position relative to each other (see p. 54). One to three hydroxyl groups (in a position) are found in the steroid core at positions 3, 7, and 12. Bile acids keep bile cholesterol in a soluble state as micelles and promote the digestion of lipids in the intestine (see p.270). Cholic add and cheno-deoxychoMc acid are primary bile acids that are formed by the liver. Their dehydroxylation at C-7 by microorganisms from the intestinal flora gives rise to the secondary bile acids lithocholic acid and deoxycholic acid. 

They are useful only in hyperlipoproteinemias involving elevated levels of LDL i.e. type Ila, lib and V. They are basic ion exchange resins. They are neither digested nor absorbed in the gut. They bind bile acids in intestine and interrupt their entero-hepatic circulation, leading to increased faecal excretion of bile salts and cholesterol. There is increased hepatic conversion of choles-terol to bile acids. More LDL receptors are expressed on liver cells leading to increased clearance of IDL, LDL and indirectly of VLDL. 

Ezetimibe Blocks sterol transporter NPC1L1 in intestine brush border Inhibits reabsorption of cholesterol excreted in bile decreases LDL and phytosterols Elevated LDL, phytosterolemia Oral duration 24 h Toxicity Low incidence of hepatic dysfunction, myositis... 

The ring structure of cholesterol cannot be metabolized to C02 and HfeO in humans. Rather, the intact sterol nucleus is eliminated from the body by conversion to bile acids and bile salts, which are excreted in the feces, and by secretion of cholesterol into the bile, which transports it to the intestine for elimination. Some of the cholesterol in the intestine is modified by bacteria before excretion. The primary compounds made are the isomers coprostanol and cholestanol, which are reduced derivatives of cholesterol. Together with cholesterol, these compounds make up the bulk of (neutral fecal sterols. 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Chylomicrons are assembled in intestinal mucosal cells and cany dietary triacylglycerol, cholesterol, fat-soluble vitamins, and cholesteryl esters (plus additional lipids made in these cells) to the peripheral tissues (Figure 18.16). 

The plasma lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They function to keep lipids (primarily triacylglyc-erol and cholesteryl esters) soluble as they transport them between tissues. Lipoproteins are composed of a neutral lipid core (containing triacylglycerol, cholesteryl esters, or both) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol. Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily, triacylglycerol) plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs, thus making the chylomicrons functional. Apo C-ll activates lipoprotein lipase, which degrades the... 

Synthesis of lipids from carbohydrates is an efficient process, which occurs largely in the liver and also in intestinal epithelial cells.6 The newly synthesized triacylglycerols, together with smaller amounts of phospholipids and cholesterol, combine with specific apolipoproteins, which are also synthesized in the liver, to form very low density lipoprotein (VLDL) particles which are secreted into the blood stream. 

Cholesterol is both absorbed from the intestinal tract and synthesized from acetate via squalene, principally in the liver. The quantities produced are substantial. Daily biosynthesis is 600 mg, and dietary uptake may supply another 300 mg.182 Not only is there a large amount of cholesterol in the brain and... 

Dietary cholesterol, together with triacylglycerols, is absorbed from the intestinal tract and enters the large lipoprotein chylomicrons (see Fig. 21-1). Absorption of cholesterol is incomplete, usually amounting to less than 40% of that in the diet. Absorption requires bile salts and is influenced by other factors.186 As it is needed cholesterol is taken from the plasma lipoproteins into cells by endocytosis. Much of the newly absorbed cholesterol is taken up by the liver. The liver also secretes cholesterol, in the form of esters with fatty acids, into the bloodstream. 

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... 

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. 

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