Sterol fecal excretion

Czubayko F, Beumers B, Lammsfuss S, Lutjohann D, von Bergmann (1991) A simplified micro-method for quantification of fecal excretion of neutral and acidic sterols for outpatient studies in humans. J Lipid Res 32 1861-1867... 

There are several hypotheses to explain the NSP action on plasma cholesterol, including enhanced bile acid and neutral sterol excretion, the slowing of fat and cholesterol absorption and direct inhibition of hepatic cholesterol synthesis by propionate formed by large bowel fermentation of NSPs. Whole body cholesterol homoeostasis represents a balance between influx and loss. Cholesterol influx can come from dietary intake and de novo synthesis. Losses occur through the sloughing of epithelial cells and through the fecal excretion of nonabsorbed dietary cholesterol and biliary steroids (bile acids and neutral sterols). Bile acids are generally recovered in the ileum, and those that are not absorbed are excreted in the feces. Any increase in bile acid excretion leads to enhanced hepatic uptake of cholesterol and its conversion to bile acids with a consequent depletion of the plasma cholesterol pool. 

Various mechanisms have been proposed to explain the hypocholesterolemic effect of GA (Annison et al., 1995 Tiss et al., 2001). Some studies have suggested that the viscosity of fermentable dietary fiber contributes substantially to the reduction of lipids in animals and humans (Gallaher et al., 1993 Moundras et al., 1994). However, other studies suggested that this property is not related to plasma lipids (Evans et al., 1992). The mechanism involved is clearly linked to increased bile acid excretion and fecal neutral sterol or a modification of digestion and absorption of lipids (Moundras et al., 1994). 

Trautwein, E. A., Rieckhoff, D., Kunath-Rau, A., and Erbersdobler, H. F. (1998). Psyllium, not pectin or guar gum, alters lipoprotein and biliary bile acid composition and fecal sterol excretion in the hamster. Lipids 33, 573-582. 

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. 

Key words Cholesterol absorption, phytosterols, cholesterol excretion, reverse cholesterol transport, ACAT, CEL, inhibitors, bile acids, fecal sterols, dual label, obesity, cardiovascular disease. 

Feces collection return the mice to their respective cages and collect feces for 24 h (see Note 3). Longer collection times have the potential to underestimate absorption since some absorbed cholesterol will end up in HDL and subsequently be taken up by the liver, transported to the bile, and secreted into the intestine. However, semi-purified diets are usually very low in fiber, which may reduce intestinal motility. If necessary, sterol transit time is measured in a preliminary experiment where only radiolabeled phytosterol is given and total fecal output is collected on days 1, 2, and 3. Sterols are quantitatively extracted (see below Section 3.1.3) and the time for 90% excretion determined. 

Tissue analysis after the 24 h fecal collection, animals are euthanized and any tissues of interest (e.g., for toxicology analysis, such as plasma, liver, kidney, heart, spleen) are harvested. Alternatively, if the mice are precious, they can be used again since the procedure is noninvasive. If the systemic presence of radiolabeled cholesterol does not compromise the second use, little delay is necessary. However, the mice will continue to excrete radiolabeled sterols at detectable levels for 2-3 weeks so bedding must be collected and segregated as contaminated waste. 

The mass of internal standards and analytes of interest in each sample are determined from the appropriate standard curves (mass vs. AUC). The total mass of excreted cholesterol and related sterols is calculated from the 5a-cholestane peak (i.s.) in each sample sterol mass per 0.5 g feces = sterol massGC x 40/i.s. masscc- The total excreted per 3 days is then calculated from the total fecal mass collected. Data are finally reported as mass (or moles) excreted per day per gram body weight. 

An increased cholesterol excretion, degradation, and decreased synthesis may explain the lower hepatic cholesterol concentration reported in exercised versus sedentary rats. In support of the former, Gollnick and Simmons (73) reported that exercised rats excreted significantly more fecal sterol than sedentary rats. 

Increased excretion of cholesterol is thought to be the mechanism for reducing serum cholesterol. Several investigators have reported increased fecal fat (7,19), sterols (7,9,19.26) or bile acids (7,9, 29,30). Kay and Truswell T) reported significant increases in fecal fat excretion, averaging 44% fecal cholesterol. 

HPMC modulates plasma lipoprotein profiles and hepatic lipid levels. HPMC is not absorbed by the body, but its presence in the intestinal lumen increases fecal fat, sterol, and bile acid excretion, which results indirectly in changes in hepatic lipid metabolism. In recent studies of hepatic gene... 

An interrupted enterohepatic circulation of cholesterol itself is seen in malabsorption (119), very little extra bile salts being lost. Under these conditions, the bile acid fluxes to and from the liver are probably normal, the return of cholesterol being markedly reduced and the biliary secretion normal or increased. Thus (a) cholesterol synthesis is increased, (b) bile acid synthesis is normal or slightly elevated, and (c) serum cholesterol is low due to augmented catabolism of cholesterol via fecal neutral sterol excretion. The relationship between bile acid and cholesterol metabolism under different conditions in which cholesterol synthesis is altered is illustrated in Table I. 

Cholesterol and fat-soluble vitamins require bile acid induced micellar solubilization for absorption, which takes place in the upper small intestine (c/. 32,116-118). Accordingly, in bile salt deficiency states, cholesterol absorption should be markedly impaired and fecal neutral sterol excretion increased. The fact that fecal neutral steroid excretion on a low-cholesterol diet is actually normal, as after ileal resection, ileal bypass, and cholestyramine treatment, or even decreased, as in cirrhosis of the liver or biliary occlusion (11), is due to a markedly reduced biliary secretion of cholesterol. In gluten enteropathy, in which no excessive bile salt loss usually exists, fecal neutral sterol excretion is markedly augmented (119). However, in occasional cases in which fecal bile salt elimination is markedly enhanced, the fecal neutral steroid excretion is quite normal, probably owing to decreased biliary cholesterol secretion as a consequence of low biliary bile salt secretion. Detailed information on the role of bile salts in both intraluminal and mucosal phases of fat and sterol absorption is presented in many recent reviews (6,10,113,114,117). 

Administration of cholestyramine to triglyceridemic patients usually has no effect on serum cholesterol. Yet a marked increase is seen in fecal bile acid elimination, the increment showing, in contrast to the results in Fig. 3, no distinct positive correlation with initial bile acid values (88). Furthermore, a cholestyramine-induced increase in fecal bile acid excretion was almost constantly associated with a decrease in neutral sterol elimination despite an apparent reduction of cholesterol absorption. Thus, under these conditions, biliary secretion of cholesterol was probably markedly decreased, particularly because cholesterol production in the intestinal mucosa was obviously enhanced by the reduction of intraluminal bile salt concentration (92,98). 

Fecal bile acid elimination is markedly reduced in patients with liver cirrhosis (11,182,191), even if icterus and signs of biliary obstruction are absent (11,182). Since, in addition, the urinary excretion of bile acids is quantitatively, if not proportionally (81), negligible, it can be concluded that the overall bile acid synthesis is markedly depressed in liver cirrhosis (182). The administration of cholestyramine, which is associated with reduction of both serum bile acids (188,192,193) and urinary bile acids (88,182), augmented the fecal bile acid excretion to a very small extent only (182). This indicates that the ability of the parenchymal cells to increase their bile acid production is clearly decreased compared to that of normal subjects. Though the fecal neutral sterol excretion was also increased by cholestyramine, only a relatively small decrease in serum cholesterol was found, suggesting that the patients still were able to increase their cholesterol production (182). 

Fig. 4. Correlation of fecal bile acid excretion with the following 1, fecal fat, 2, 3, and 4, jejunal micellar fat and bile acids, and jejunal total cholesterol, respectively, calculated for amounts found in the intestinal pool in which 136 mg of )5-sitosterol administered in the test meal was dispersed. 5, Serum methyl sterol (diunsaturated dimethyl sterol), used as an indicator of augmented cholesterol synthesis (see reference 11). 6, Serum cholesterol., Patients with incomplete ileal resection (25-50 cm of the very terminal ileum intact, 1-2 m of the more proximal gut removed) , complete ileal resection 4, extensive intestinal resections with severe malnutrition (the values omitted from calculations in 5).

Clofibrate is a widely used hypolipidemic agent whose mode of action, like that of nicotinic acid, has not been unequivocally established (21). In the earliest studies of the effect of this compound on fecal steroid excretion (22), it was concluded that excretion of sterols was increased but that of bile acids was not. The ratio of glycocholanic/taurocholanic acid was unaffected (23). Grundy et al. (24) reported that this drug reduced fecal bile acid excretion in their patients. 

Cholestyramine is a high molecular weight anionic exchange resin which, as the chloride salt, is used to absorb bile acids. In the dog (26), this material, when fed at the level of 25 g/day, was shown to increase fecal sterols by 85 % and fecal bile acids by 160% and to reduce cholesterol levels by 22%. Rate fed 2 % of cholestyramine in the diet showed a three- to fourfold increase in bile acid excretion, and the increase was all in the dihydroxycholanic acid fraction (27). In mice (28), this resin decreased the time for bile acid turnover from 5 to 1.25 days. Fecal neutral sterols were increased by 37%. Pigs fed 2-4% cholestyramine showed a marked increase in bile acid excretion (29). 

Rats on 1 % cholesterol Effective hypocholesterolemic effect higher excretion of fecal sterols and bile acids [104]... 

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