Hypercholesterolemia cholesterol absorption

Cholesterol absorption inhibition. Fiber, administered in ration of male hamsters at a concentration of 7.5% of diet, was inact-Iygpoo33 Seeds, administered orally to 20 male adults with mild hypercholesterolemia at a dose of 5.1 g/day for 40 days, were active . 

The effect of ezetimibe on cholesterol absorption is constant over the dosage range of 5-20 mg/d. Therefore, a single daily dose of 10 mg is used. Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. It is also effective in patients with phytosterolemia. Ezetimibe is synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone. 

The most notable discovery in the area of monocyclic azetidin-2-ones is its development as cholesterol absorption inhibitors. The monocyclic azetidin-2-one 559, earlier known as SCH58235, was discovered to have potential cholesterol absorption inhibition property in the late 1990s <1998JME973>. This compound is now in clinical application with the name ezetimibe to treat hypercholesterolemia <2004JME1>. It has been observed recently that the new nonhydrolyzable glycoside 560, prepared using the scaffold of ezetimibe, is also a potent inhibitor of cholesterol absorption <2004AGE4653>. 

The primary goal of therapy is the control of the hypercholesterolemia and prevention of atherosclerotic cardiovascular disease. Patients with heterozygous FH can usually be successfully treated with medications to lower the LDL cholesterol to acceptable levels (Table 14-2). They are generally responsive to treatment with statins, alone or in combination with other drugs, such as bile acid sequestrants (such as cholestyramine) or cholesterol absorption inhibitors (such as ezetimibe) that act additively to upregulate the expression of the functioning LDL receptor as described in the Biochemical Perspectives section. In a few cases, a more aggressive treatment with LDL apheresis (discussed in this section) may have to be considered in order to reach acceptable LDL cholesterol levels. 

Burnett, J. R., Huff, M. W. Cholesterol absorption inhibitors as a therapeutic option for hypercholesterolemia. Expert Opin. Investig. Drugs 2006, 15, 1337-1351. 

The cloning of ACAT-2 (R.A. Anderson, 1998 S. Cases, 1998 R Oelkers, 1998) revealed a protein of simitar size to ACAT-1, with a novel N-terminus but a C-terminus highly similar to ACAT-1. In adult humans, ACAT-2 is expressed in the apical region of intestinal enterocytes and in hepatocytes. Disruption of the ACAT-2 gene in mice led to dramatic reduction in cholesterol absorption and prevention of hypercholesterolemia (A.K.K. Buhman, 2000). The data suggest that, in humans, ACAT-1 plays a critical role in foam-cell formation and cholesterol homeostasis in extrahepatic tissues, whereas ACAT-2 has an important role in absorption of dietary cholesterol [29]. Interest in ACAT inhibitors as a therapeutic strategy has been revived by liver-specific knockdown of ACAT-2 in atherosclerotic-prone mice, which significantly reduced aortic atherosclerotic lesions (T.A. Bell, 2006). 

Cholesteryl esters are quantitatively minor constituents (5-15% of total lipids) of VLDLs but the amount of cholesteryl esters relative to TG in VLDLs increases when rats are fed a high cholesterol diet. The esterification of cholesterol is mediated by two distinct acyl-CoA cholesterol acyltransferases (ACATs) [11]. Inhibition of cholesterol esterification with an ACAT inhibitor in hepatocytes decreased apo B secretion in some studies but not in others. For example, severe reduction in cholesteryl ester content of hepatoma cells decreased apo B secretion, whereas increased cholesteryl ester content did not stimulate apo B secretion. In mouse liver and intestine, the majority of cholesteryl esters are made by ACAT2. Nevertheless, normal quantities of apo B-containing lipoproteins are produced in mice lacking ACAT2 despite the absence of essentially all hepatic ACAT activity. However, ACAT2-deficient mice exhibit reduced intestinal absorption of cholesterol and are resistant to diet-induced hypercholesterolemia (R.V. Farese, 2(X)0). Thus, the observed reduction of plasma cholesterol in response to ACAT inhibitors is probably due to decreased cholesterol absorption rather than decreased VLDL secretion. 

Several saponins have been shown to inhibit intestinal cholesterol absorption and reduce plasma cholesterol concentrations in a variety of experimental models and are therefore of pharmacologic utility in the treatment of hypercholesterolemia. 

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... 

Hypercholesterolemia is an important risk factor for cardiovascular disease. The hypocholester-olemic action of chitosan can be explained to be due to the decrease in cholesterol absorption and interference with bile acid absorption, a mechanism similar to those of dietary fiber constituents. Here, the cholesterol-lowering effects of chitin, chitosan, and their derivates are reported based on animal and clinical studies. 

Chitosan also has hypocholesterolemic effects and acts as an adjuvant to weight loss in rat studies [31,32]. Studies have reported that chitosan reduced the concentration of plasma cholesterol in animals [33,34] and type If diabetes patients in combination with hypercholesterolemia [33]. This property is being attributed to the positive charge of the molecule that binds to fatty acids (released from consumed fat) and bile salt components, which results in disrupted lipid absorption in the gut [5]. Also, chitosan is dissolved in the stomach, emulsifying the fat and forming a gel in the intestine which entraps fat and prevents intestinal absorption [35,36]. Chitosan forms a floccule in the duodenum which entraps dietary oil [37]. However, these effects are still controversial [31,38,39]. Actually, van Bennekum et al. [32] suggested that the incorporation of chitosan in the diet of rats reduces cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. 

This specifity for cholate or its conjugates on cholesterol absorption has also been demonstrated by modification of biliary bile acid composition by hormonal perturbations (see[40]). For example, in hypothyroid rats, there is a diminished biliary output of bile acids[41], and a shift in the ratio of biliary cholate and cheno-deoxycholate. This ratio is approximately 3 1 cholate to cheno-deoxycholate in normal rats and is shifted dramatically (9 1) in hypothyroid rats[42]. As might be expected, this hormonal deficiency results in multiple alterations in overall physiology, among which are hypercholesterolemia and increased absorbability of choles-terol[40]. Conversely, administration of thyroid hormones (L-thyroxine or triiodothyronine) results in diminished levels of biliary cholate, and proportional increases in chenodeoxycholate. 

Plant sterols - especially B-sitosterol, given at the dose of 10-15g/day - are known to reduce serum cholesterol levels by inhibiting cholesterol absorption[137,138]. This effect could be due either to competitive inhibition for mucosal uptake or to crystallization and coprecipitation of the sterols or to other unknown mechanisms. Mattson et al. recently showed that when 3-sitosterol was dissolved in the test meal together with cholesterol - so that both the sterols were presented simultaneously to the intestinal mucosa a much smaller amount of the plant sterol (Ig) was sufficient to induce a significant (42% on average) decrease of cholesterol absorption[139]. If confirmed, these findings might render much easier the use of phytosterols in the treatment of hypercholesterolemia. 

The first description of the use of plant stanols to lower plasma cholesterol levels in humans was by Heinemann etal (1986) in a small uncontrolled study. They showed that the administration of capsules of sitostanol dispersed in monoacylglycerol and sunflower oil at a dose of 1.5g/day lowered LDL cholesterol levels by 15%. Similar concentrations of sitosterol and sitostanol infused directly into the small intestine decreased cholesterol absorption by 50% and 85%, respectively (Heinemaim et al, 1991). Becker et al (1993) obtained impressive results with low-dose sitostanol in an uncontrolled study with 9 children suffering from familial hypercholesterolemia. LDL cholesterol levels decreased by 33% when the children consumed 1.5 g sitostanol daily, and by 20% when they consumed 6 g sitosterol daily, suggesting that sitostanol is more effective than sitosterol at lowering LDL cholesterol levels. 

Ezetimibe is a dmg with cholesterol absorption inhibitor properties used to treat hypercholesterolemia. Its active form, (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one, was successfully obtained via microbial diastereoselective reduction of (3R,4S)-l-(4-fluorophenyl)-3-[3-oxo-3-(4-fiuorophenyl)-propyl]-4-(4-hydroxyphenyl)azetidin-2-one using whole cells of Rhodococcus fascians M022 (Figure 13.5b) [19]. Conversion of 94% was obtained after 4h in highly diluted system (0.1 g/1 substrate) with 20% cell suspension, along with excellent de value (99.9%). 

Cholesterol Transport Protein Inhibitor Ezetimibe is the first hypolipidemic agent to act by blocking the absorption of dietary cholesterol at the intestinal level. It represents a novel treatment option for patients with hypercholesterolemia, alone or in combination with statins (Figure 8.60). 

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... 

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). 

A concern has been raised that phytosterol doses that are effective for cholesterol reduction may impair the absorption and lower blood concentrations of fat-soluble vitamins and antioxidants. A number of studies showed that phytosterols had no effect on plasma concentrations of vitamin D, retinol, or plasma-lipid-standardized alpha-tocopherol. Moreover, the reports of the effect of phytosterols on concentrations of blood carotenoids (lutein, lycopene, and alpha-carotene) are controversial. There seems to be general agreement that phytosterol doses >1 g/d significantly decrease LDL-C standardized beta-carotene concentrations however, it remains to be determined whether a reported 15-20% reduction in beta-carotene due to phytosterol supplementation is associated with adverse health effects. Noakes et al. found that consumption of one or more carotenoid-rich vegetable or fruit servings a day was sufficient to prevent lowering of plasma carotenoid concentrations in 46 subjects with hypercholesterolemia treated with 2.3 g of either sterol or stanol esters. 

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