Cholesterol metabolism Absorption

Fernandez LM, Lin ECK, Trejo A and McNamara DJ. 1994. Prickly pear (Opuntia sp.) pectin alters hepatic cholesterol metabolism without affecting cholesterol absorption in guinea pigs fed a hypercholesterolemic diet. J Nutt 124 817-824. 

Hypolipidemic activity. Seed hull, administered to mice at a dose of 2.5% of diet for 18 weeks, was inactive " . The husk, administered orally to male Hartley guinea pigs at doses of 7.5 or 10 g/100 g of Plantago ovata for 4 weeks, exerted a hypolipidemic effect by affecting bile acid absorption and altering hepatic cholesterol metabolism Insulin release inhibition. Seed administered orally to 18 patients with noninsulin-dependent diabetes at a dose of 13.6 g/day lowered insulin levels by 17% . 

In addition to treatment with the statins, hypercholesterolemia is sometimes treated with the use of nonabsorbable anion-exchange resins like cholestyramine (5.13) and colestipol, which sequester bile acid in the intestine, excrete them, and thus increase their synthesis in the liver by a feedback mechanism. Increased bile acid synthesis increases cholesterol metabolism and also decreases LDL concentrations. Unfortunately, these resins interfere with the absorption of other fats and fat-soluble vitamins (A, D, E, and K). They... 

Harwood, H.J., Jr., Chandler, C.E., Pellarin, L.D., Bangerter, F.W., Wilkins, R.W., Long, C.A., Cosgrove, P.G., Malinow, M.R., Marzetta, C.A., Pettini, J.L., Savoy, Y.E., and Mayne, J.T. 1993. Pharmacologic consequences of cholesterol absorption inhibition Alteration in cholesterol metabolism and reduction in plasma cholesterol concentration induced by the synthetic saponin /Migogenin cellobioside (CP-88818 tiqueside). J. Lipid Res. 34, 377-395. 

In this light, cholesterol absorption has received intense focus for several decades. Although the various statins lower LDL by decreasing endogenous cholesterol synthesis, another approach to prevent excess cholesterol accumulation is to reduce absorption of dietary cholesterol. Doing so also prevents reabsorption of biliary cholesterol, which can have a major impact on overall cholesterol metabolism since recirculation of biliary cholesterol represents a large portion of the cholesterol that transits through the intestine. For recent reviews on mechanisms of cholesterol and lipid absorption, see ref. (1-3). 

The search for intestinal cholesterol transporters extended for many years, beginning with a debate about whether or not it was even a protein-facilitated process (4, 5). The pancreatic enzyme carboxyl ester lipase (CEL, also called cholesterol esterase) was believed to be important to this process (6,7) and several companies devoted considerable resources to the development and testing of compounds to inhibit CEL, with mixed results (8-10). These efforts were abandoned in the mid-1990s, however, after studies with gene-knockout mice demonstrated that the enzyme was important only for absorption of cholesteryl ester (11, 12), which is a minor component of dietary cholesterol and is present at very low levels in bile. Interestingly, CEL is also found in liver where it has been shown to affect HDL metabolism (13). Thus, it may ultimately play an important role in cholesterol metabolism and may yet prove to be a useful drug target for CVD treatment (Camarota and Howies, unpublished). 

The proportions of delta 8-cholesterol and desmosterol in the serum rose while those of cholestanol, campesterol and sitosterol dropped, implying a decreased absorption of cholesterol and a compensatory increase in its synthesis. High basal precursor sterol proportions were predictive of a large decrement in titer of LDL cholesterol. It appeared that partial substitution of normal dietary lipid consumption with sitostanol was a safe and effective therapeutic measure for children with FH (Lees et al., 1977 Wang and Ng, 1999). The effect of a small amount of sitosterol, sitostanol and sitostanol esters dissolved in rapeseed oil on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and various apolipoprotein E phenotypes on a rapeseed oil diet showed a diminution in TC and LDL-cholesterol levels in the serum (Gylling and Miettinen, 1994). 

Other conditions previously mentioned in this chapter, such as cancer, immunocompetence and interferon production, antihistamine eflFects in colds, increased iron absorption, eflFects on cholesterol metabolism, and nitrosamine blocking, were studied at higher than RDA dosage levels. These many situations require additional research study to determine what the minimum levels are to attain the optimal health condition. 

Recent investigations into the mechanism of action of these bile acids indicate that ursodeoxycholic acid has certain advantages over chenodeoxycholic acid in the context of the overall homeostasis of cholesterol metabolism (F6). In contrast to chenodeoxycholic acid, ursodeoxycholic acid does not suppress bile acid synthesis (H7), possibly because the a-orientation of the 7-hydroxyl group of chenodeoxycholic acid is required to inhibit cholesterol 7a-hydroxylase activity. Thus, cholesterol breakdown into bile acids is not reduced by ursodeoxycholic acid. Other favorable factors are that ursodeoxycholic acid has a reduced capacity to solubilize cholesterol into micellar solution compared to chenodeoxycholic acid and intestinal cholesterol absorption is decreased by this bile acid (F6, H7). However, in gallbladder bile the relative limitation of ursodeoxycholic acid for micellar solubilization of cholesterol is compensated for by an ability to transport... 

Harwood HJ, Chandler CE, Pellatin LD, Bangerter FW, Wilkins RW, Long CA, Cosgrove PG, Malinow MR, Marzetta CA, Pettini JL, Savoy YE, Mayne JT (1993) Pharmacologic Consequences of Cholesterol Absorption Inhibition Alteration in Cholesterol Metabolism and Reduction in Plasma Cholesterol Concentration Induced by the Synthetic Saponin /V-Tigogcnin Cellobioside (CP-88818 Tiqueside). J Lipid Res 34 377... 

Sesame oil affects cholesterol mobility in the human organism. To study the potential activity of other kinds of compounds, Hirose et al. [222] analysed the effects of sesamin, a lignan present in the oil, on various aspects of cholesterol metabolism, and they observed that a diet with sesamin reduced the concentration of serum and liver cholesterol except in the group free of cholesterol. Sesamin decreased lymphatic absorption of cholesterol and increased the fecal excretion of the neutral but not the acidic form. At the liver level, there was a significant reduction in the activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase, but the activity of hepatic cholesterol 7a-hydroxylase and alcohol dehydrogenase were not affected. Microscopic histological examination did... 

When food supplies are plentiful, hormonal activation leads to fatty acid, triacylglycerol, and cholesterol synthesis. A high dietary intake and intestinal absorption of cholesterol will compensatorily reduce the rate of hepatic cholesterol synthesis, in which case the liver acts as a recycling depot for sending excess dietary cholesterol to the peripheral tissue when needed as well as accepting cholesterol from these tissues when required. The pathways of cholesterol metabolism were discussed in Chapter 34. 

The effects of fucoxanthin-rich seaweed extract (Fx-SEE) on body weight gain and lipid metabolism in HF-fed C57BL/6J mice were investigated by Jeon et al. (2010). They demonstrated that Fx-SEE affects the plasma and hepatic lipid profile, fecal lipids, and body fat mass, and alters hepatic cholesterol metabolism, FA synthesis, and lipid absorption in mice. 

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. 

Bile acids have two major functions in man (a) they form a catabolic pathway of cholesterol metabolism, and (b) they play an essential role in intestinal absorption of fat, cholesterol, and fat-soluble vitamins. These functions may be so vital that a genetic mutant with absence of bile acids, if at all developed, is obviously incapable of life, and therefore this type of inborn error of metabolism is not yet known clinically. A slightly decreased bile acid production, i.e., reduced cholesterol catabolism, as a primary phenomenon can lead to hypercholesterolemia without fat malabsorption, as has been suggested to be the case in familial hypercholesterolemia. A relative defect in bile salt production may lead to gallstone formation. A more severe defect in bile acid synthesis and biliary excretion found secondarily in liver disease causes fat malabsorption. This may be associated with hypercholesterolemia according to whether the bile salt deficiency is due to decreased function of parenchymal cells, as in liver cirrhosis, or whether the biliary excretory function is predominantly disturbed, as in biliary cirrhosis or extrahepatic biliary occlusion. Finally, an augmented cholesterol production in obesity is partially balanced by increased cholesterol catabolism via bile acids, while interruption of the enterohepatic circulation by ileal dysfunction or cholestyramine leads to intestinal bile salt deficiency despite an up to twentyfold increase in bile salt synthesis, to fat malabsorption, and to a fall in serum cholesterol. 

During the course of a study of the effects of polyunsaturated fatty acid derivatives on cholesterol metabolism, Nakatani and his associates [432] found that amides of linoleic acid showed a pronounced cholesterol-lowering effect in mice, rats, and rabbits which had been fed cholesterol. However, addition of these amides to a cholesterol-free diet did not show any significant effect on cholesterol levels. Metabohc studies have suggested that iV-cyclohexyl linoleamide (CXCI) interferes with the absorption of cholesterol from the intestine. The antiatherosclerotic effect of compound CXCI has also been studied by Kritchevsky and Tepper [433]. They have found that the administration of 600-900 mg/day of CXCI to rabbits maintained on an atherogenic dief led to reduced atheromata however, it was found to be ineffective at a dose of300mg/day. This lower dose has been found to reduce serum and hver cholesterol levels [433]. 

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...

The mode of action of sitosterol, which differs in structure from cholesterol by possession of an ethyl group on C-24, has not been established. In contrast to cholesterol, intestinal absorption of sitosterol has been shown to take place in only very small quantities (Schoenheimer 1929,1932, Best 1956, Schettler 1961) and amounts to about 5% of administered sitosterol, (Gould 1955). According to one theory sitosterol interferes with the absorption of cholesterol. If cholesterol and sitosterol are administered simultaneously, the absorption of the former is markedly decreased (Hernandez et al. 1953) only one-third of the cholesterol is absorbed if both substances are administered in equal parts, while cholesterol absorption is nil when cholesterol and sitosterol are fed in the proportion of 1 7 (Pollak 1953). Mixed crystal formation may be responsible for this effect, as suggested by the in vivo and in vitro studies of Davis (1955) and of Hudson and co-workers (1959), who found crystals with an X-ray diffraction pattern different from either cholesterol or sitosterol, and suspected the presence of a less-dispersible compound. The assumption of Swell et al. (1954) that there is competitive inhibition of esterification of cholesterol by sitosterol, has been refuted by Blomstrand and Ahrens (1958), and the suggestion of Glover et al. (1957) of competition for acceptor lipoproteins is unproved. Gerson and Shorland (1963), on the basis of isotopic studies in rats, considered the effect of beta-sitosterol on cholesterol absorption to be less important, and discussed the effects of the sterol on cholesterol metabolism and on the cholesterol content of different tissues. 

The interest of drugs interfering with cholesterol metabolism, is based on the assumption that high blood levels of this sterol are correlated with atherosclerosis. In fact, hypercholesterolaemia is considered a major risk factor for coronary heart disease. It is possible to act on cholesterol metabolism with drugs interfering either with cholesterol absorption and biosynthesis or with its catabolism and excretion. 

Another possible mechanism for the effect of dietary carbohydrates on cholesterol metabolism is that the carbohydrates affect the absorption of cholesterol. Dietary fructose with cholate gave rise to a hypercholesterolemia in rats, cornstarch was not very effective in this regard, and sucrose and dextrose were intermediate (Portman et al., 1956b). Sucrose favors cholesterol reabsorption in chicks when compared with glucose (Grant and Fahrenbach, 1957) and in rabbits lactose gives rise to more reabsorption than sucrose (Wells and Anderson, 1959). 

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