Absorption of cholesterol

in the normal intestine with an intact enterohepatic circulation of bile acids, it is the product of the maximum solubility of the various lipids and their respective passive permeability coefficients that primarily dictates the rates of uptake into the intestinal mucosa. Hence, over 100 g of medium- and long-chain-length fatty acids 

A second major source for cholesterol in the intestinal epithelial cell is de novo synthesis from acetyl-CoA. This section reviews the methods available for measuring such synthesis and discusses the localization and regulation of this process. 

Older techniques used to measure the rates of cholesterol synthesis in the small bowel have led to errors with respect to the importance, localization and regulation of this process. For example, the specific activity of various C-labeled precursors 

Similar problems have compUcated the quantitation of HMG-CoA reductase activity as a measure of the rate of cholesterol synthesis. For example, it has not been established as firmly for the intestine as for the hver that this enzyme is rate limiting to the overall synthesis of the cholesterol molecule [23]. Furthermore, HMG-CoA reductase in both the intestine and liver is subject to a phosphorylation-dephosphorylation reaction that modifies enzyme activity and is involved in the activation of an inactive (phosphorylated) to an active (dephos-phorylated) form during homogenization of the mucosa [24,25]. Finally, HMG-CoA reductase is incompletely recovered from the mucosa during preparation of micro-somes [26,27] and is very sensitive to inactivation by proteases present in the intestine [28]. These various technical problems have led to considerable confusion with respect to various aspects of intestinal cholesterol synthesis and have made it difficult to interpret quantitatively some of the results presented below. 

More direct evidence that cholesterol itself regulates sterol synthesis in the intestine has been obtained in studies using various in vitro techniques such as organ culture of intestinal mucosa. In such a system, cholesterol dissolved in ethanol 

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Historically, the absorption of lipid-soluble nutrients has been considered to be carrier-independent, with solutes diffusing into enterocytes down concentration gradients. This is true for some lipid-soluble components of plants (e.g. the hydroxytyrosol in olive oil Manna et al., 2000). However, transporters have been reported for several lipid-soluble nutrients. For example, absorption of cholesterol is partly dependent on a carrier-mediated process that is inhibited by tea polyphenols (Dawson and Rudel, 1999) and other phytochemicals (Park et al., 2002). A portion of the decreased absorption caused by tea polyphenols may be due to precipitation of the cholesterol associated with micelles (Ikeda et al., 1992). Alternatively, plant stanols and other phytochemicals may compete with cholesterol for transporter sites (Plat and Mensink, 2002). It is likely that transporters for other lipid-soluble nutrients are also affected by phytochemicals, although this has not been adequately investigated. 

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. 

Ezetimibe reduces LDL cholesterol by an average of 18% (Table 9-8). However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol. 

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. 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

About 1 g of cholesterol is ingested by adults each day in developed countries. A similar amount enters the lumen via the bile, synthesised from acetyl-CoA in the liver, is also released from sloughed epithelial cells. Absorption of cholesterol also occurs from the mixed micelles. Within the enterocyte, it is esterified and the cholesterol ester is incorporated into the chylomicrons. 

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. 

Ezetimibe/Simvastatin (Vytorin) [Antilipemic/HMG CoA Reductose Inhibitor] Uses H rp cholest olemia Action X Absorption of cholesterol phytost ol w/ HMG-CoA reductase inhibitor Dose 10/10-10/80 mg/d PO w/ cyclosporine or danazol 10/10 mg/d max w/ amio-darone or verapamil 10/20 mg/d max -1- w/ sev e renal insuff Caution [X, -] w/ CYP3A4 inhibitors (Table VI-8), gemfibrozil, niacin >lg/d, danazol, amiodarone, verapamil Contra PRG/lactation livCT Dz, t LFTs Disp Tabs SE HA, GI upset, myalgia, myopathy (muscle pain, weakness, or tendOTiess w/ CK 10 x ULN, rhab-domyolysis), Hep, Infxn Interactions t Risk of myopathy W7 clarithromycin, erythromycin, itraconazole, ketoconazole EMS None OD Sxs unknown symptomatic and supportive... 

CN097 Satchithanandam, S., M. Reicks, R. J. Calvert, M. M. Cassidy, and D. Kritchevsky. Coconut oil and sesame oil affect lymphatic absorption of cholesterol and fatty acids in rats. J Nutr 1993 123(11) 1852-1858. 

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. 

Infrared Spectra. The effect of composition on infrared absorption of cholesterol-lecithin mixtures was striking in two regions of the spectrum—near 2.8 and 9.2 microns—which are associated with O-H and P-O-C stretching frequencies, respectively (Figure 4). 

The infrared spectra of systems containing lactoside could not be analyzed in a similar way because the absorption of the hydroxyl groups of the sugar masked the absorptions of cholesterol at 2.8 microns and of the P-O-C group of lecithin between 8 and 10 microns. 

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. 

One of the best therapeutic approaches may be to prevent absorption of cholesterol from the intestines by inclusion of a higher fiber content in the diet.66 Supplementation with a cholesterol-binding resin may provide additional protection. Plant sterols also interfere with cholesterol absorption. Incorporation of esters of sitostanol into margarine provides an easy method of administration. Supplemental vitamin E may also be of value.q Another effective approach is to decrease the rate of cholesterol synthesis by administration of drugs that inhibit the synthesis of cholesterol. Inhibitors of HMG-CoA reductase,s hh (e.g., vaLostatin) iso-pentenyl-PP isomerase, squalene synthase (e.g.,... 

Loest HB, Noh SK, Koo SI. 2002. Green tea extract inhibits the lymphatic absorption of cholesterol and -tocopherol in ovariectomized rats. J Nutr 132 1282-1288. 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

Absorption of cholesterol in the small intestine contributes to maintaining whole-body cholesterol homeostasis, yet the mechanisms of absorption have not been completely defined. For many years it was believed that cholesterol, a normal component of cell membranes, simply diffused through the brush border membrane of enterocytes (Grundy, 1983 Westergaard and Dietschy, 1974). However, the discovery of specific transporters, receptors,... 

Biliary cholesterol is entirely unesterified and flows into the small intestine as a component of bile. The other major components of bile are phosphatidylcholine (lecithin) and bile acids. Absorption of cholesterol and other lipids depends on their ability to form micelles within the intestinal lumen. 

Ellegard, L., Andersson, H., and Bosaeus, I. 1997. Inulin and oligofructose do not influence the absorption of cholesterol, or the excretion of cholesterol, Ca, Mg, Zn, Fe, or bile acids but increases energy excretion in ileostomy subjects. Eur. J. Clin. Nutr. 51, 1-5. 

Huff, M.W. and Carroll, K.K. 1980. Effects of dietary protein on turnover, oxidation, and absorption of cholesterol, and on steroid excretion in rabbits. J. Lipid Res. 21, 546-558. 

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. 

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

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). 

Linseisen, J., Wolfram, G. 1998. Absorption of cholesterol oxidation products from ordinary foodstuffs in humans. Arm. Nutr. Metab. 42, 221-230... 

Q7 Fibre comes from the parts of plants which cannot be digested in the human gut. It may either be insoluble, for example cellulose, hemicellulose or lignins, or the soluble type, such as pectins and gums. The soluble type of fibre helps to slow absorption of cholesterol from the gut, lowers blood cholesterol and decreases the risk of coronary disease. 

Western diets are generally high in refined foods and low in fibre content. Fibre may be insoluble, for example cellulose, or soluble, for example pectin from plants. Insoluble fibre binds water, increases the bulk of the faeces and increases rapidity of transit through the intestine. Soluble fibre slows absorption of cholesterol and reduces blood cholesterol concentration. 

Ezetimibe reduces the absorption of cholesterol from the gastrointestinal tract. 

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