Cholesterol intestinal absorption

Currently available treatments against atherosclerosis include cholesterol-lowering drugs such as statins, fibrates, nicotinic acid (NA) [8-13] and the cholesterol intestinal absorption inhibitor, ezetimibe (Fig. 1) [14]. 

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. 

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). 

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. 

Van Bennekum, A. et al.. Class B scavenger receptor-mediated intestinal absorption of dietary P-carotene and cholesterol, Biochem., 44, 4517, 2005. 

The first study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption (During et al., 2005). Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 pmol/L) with or without ezetimibe (EZ Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ (lOmg/L) as follows P-C and a-C (50% inhibition) P-cryptoxanthin and LYC (20%) LUT ZEA (1 1) (7%). EZ reduced cholesterol transport by 31%, but not retinol transport. P-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on P-C transport... 

A. van Bennekum, M. Werder, S. T. Thuahnai, C. H. Han, P. Duong, D. L. Williams, P. Wettstein, G. Schulthess, M. C. Phillips, and H. Hauser, Class B scavenger receptor-mediated intestinal absorption of dietary P-carotene and cholesterol, Biochemistry 44 (2005) 4517 1525. 

Play, B. et al. (2003). Glucose and galactose regulate intestinal absorption of cholesterol. Biochem. Biophys. Res. Commun. 310(2) 446 151. 

Heinemann T, Axtmann G and Von Bergmann. K 1993. Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur J Clin Invest 23(12) 827—831. 

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. In one trial, patients receiving ezetimibe in combination with simvastatin had marginal, but not statistically significant, increases in carotid intimal-medial thickness (IMT) compared with those... 

Ezetimibe is a selective inhibitor of intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, appears to be the target of the drug. It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile. 

Plant sterols Commercially available margarines containing hydrogenated plant sterols and sterol esters (predominantly sitostanol esters), when used in place of regular margarine, can reduce LDL plasma cholesterol concentrations. The mechanism by which these compounds lower LDL cholesterol concentrations is to inhibit intestinal absorption of dietary cholesterol and cholesterol secreted into the bile. 

Ezetimibe is a selective potent inhibitor of the intestinal absorption of dietary and biliary cholesterol. A total of 432 patients were included in a pooled analysis of two phase-II studies, both lasting for 12 weeks ezetimibe was well tolerated, with an adverse events profile similar to that of placebo (1). In 668 patients who took ezetimibe with simvastatin, the adverse effects were similar to those with simvastatin alone (2). 

Noh, S.K. and Koo, S.I. 2004. Milk sphingomyelin is more effective than egg sphingomyelin in inhibiting intestinal absorption of cholesterol and fat in rats. J. Nutr. 134, 2611-2616. 

Vahouny, G.V., Chalcarz, W., Satchithanandam, S., Adamson, I., Klurfeld, D.M., and Kritchevsky, D. 1984. Effect of soy protein and casein intake on intestinal absorption and lymphatic transport of cholesterol and oleic acid. Am. J. Clin. Nutr. 40, 1156-1164. 

Ezetimibe is the first member of a new group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. 

Various modifications are reported with respect to the experimental setup (single pass or recirculated intestinal perfusion) as well as the site of blood collection, e.g. mesenteric vessels for estimation of the intestinal absorption rate (DeGraw RT, Anderson BD 2004). vs. peripheral veins for estimation of systemic availability of the candidate compound. This method is widely used for investigation of intestinal absorption of nutrients by using radioactive tracers (e.g. cholesterol, glucose) and their interference with the candidate compound (Arts et al. 2004). In addition the secretion of the candidate compound into the intestine can be studied by peripheral administration of the compound into a peripheral vein and subsequent determination of the appearance of the candidate compound in the intestinal perfusate (Merino et al. 2003 Berggren et al. 2004). Also variations are reported using chronically isolated intestinal loops in rats (Poelma et al. 1992). 

Critical to vitamin D3 action is its further metabolic conversion to more active compounds (Figure 1.3). Via its transport by DBP, vitamin D3 accumulates in the liver [48]. In rats, as much as 60-80% of an injected or oral dose of vitamin D3 locates to the liver [49-51], Intestinal absorption of vitamin D3 is in association with the chylomicron fraction via the lymphatic system. Vitamin D3 is delivered to the liver in blood from the thoracic duct only a few hours post ingestion [44], A specific portion of hepatic vitamin D3 in the rat is converted to 25-OH-D3 by a 25-hydroxylase system in the endoplasmic reticulum of hepatocytes [52, 53]. This enzyme (Km 10"8 M) is regulated to an extent by 25-OH-D3 and its metabolites. Higher concentrations of vitamin D3 are handled by a second 25-hydroxylase located in liver mitochondria [54], This enzyme, also known as CYP27, 27-hydroxylates cholesterol and thus appears less discriminating than the microsomal 25-OHase which does not use cholesterol as substrate [55, 56]. In humans, however,... 

Finckh, B. Kontush, A. Commentz, J. Flubner, C. Burdelski, M. Kohlschiitter, A. 1995. Monitoring of ubiquinol-10, ubiquinone-10, carotenoids, and tocopherols in neonatal plasma microsamples using high-performance liquid chromatography with coulometric electrochemical detection. Anal. Biochem. 232 210-216. Fleshman, M.K. Cope, K.A. Novotny, J.A. Riedl, K. Schwartz, S.J. Jones, P.J. Baer, D.J. Harrison, E.H. 2010. Efficiency of intestinal absorption of P-carotene (BC) is not correlated with cholesterol (CHL) absorption in humans. FASEB J. 24S 539.4. 

A supplementation of procyanidins from cocoa significantly decreased plasma or liver cholesterol and triglycerides in rats fed a high cholesterol diet. The capacity of procyanidins to inhibit intestinal absorption of cholesterol appeared to be one of the mechanisms (Osakabe and Yamagishi, 2009). Cocoa procyanidins had sustained benefits to reverse vascular dysfunction in diabetic patients (Balzer et ah, 2008). Such benefits had been attributed to (—)-epicatechin, which is the constituent unit of cocoa procyanidins (Schroeter et ah, 2006). Procyanidins from cacao were found to inhibit growth of human breast cancer and colonic cancer cells (Camesecchi et ah, 2002 Ramljak et ah, 2005). 

Plant sterols inhibit the intestinal absorption of cholesterol and so have a useful hypocholesterolemic action. They also inhibit endogenous synthesis of cholesterol, by inhibiting and repressing the regulatory enzyme of cholesterol synthesis, hydroxymethylglutaryl (HMG)-CoA reductase. Other compounds synthesized from mevalonate also inhibit and repress HMG-CoA reductase and have a hypocholesterolemic action, including squalene (found in relatively large amounts in olive oil), ubiquinone (Section 14.6), and the tocotrienols (Section 4.1). 

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