Cholesterol, Biliary

When Reuben et al., measured the hourly secretion rates of phospholipids, bile acids and cholesterol in obese and nonobese individuals with and without cholesterol gallstone disease, they found that the pattern of results was quite different in the obese and the nonobese gallstone carriers. The obese had hypersecretion of cholesterol but normal bile-acid output, while the nonobese had normal cholesterol secretion but a reduced bile-acid output. The authors speculated that the most likely explanation for the high biliary cholesterol secretion rates in the obese was their increased total body cholesterol synthesis. Conversely, nonobese gallstone carriers often have a reduced total bile-acid pool size, and if the enterohepatic cycling frequency of this small bile-acid pool remains unchanged (controversial), it could explain the reduced bile-acid secretion rate seen in the normal weight (nonobese) individuals. 

These results illustrate the concept that there are multiple ways by which bile may become supersaturated with cholesterol. For example, there may be (i) hyper-secretion of cholesterol, (ii) hypo-secretion of bile acids, (iii) hypo-secretion of phospholipids or (iv) some combined secretory defect. Of these, high biliary cholesterol secretion seems to be the most common disorder. 

Biliary cholesterol saturation index (CSI) in nonacromegalic patients with cholesterol GBS (CH-GBS), acromegalic patients with Octreotide-associated GBS (OT-GBS), and stone-free patients before Octreotide treatment (No OT-GBS). "Hie value of CSI = 1.0 indicates the limit of cholesterol solubility points above the line are supersaturated, whereas those below the line are unsaturated with cholesterol. (All graphs show mean values SEMs.) Data taken from reference 18. 

There are multiple ways by which an increase in the percentage DCA in bile may pre-dispose to cholesterol gallstone formation. Carulli et al. showed that DCA-rich bile induces biliary cholesterol hyper-secretion when compared with other bile acids (Graph 8.6). This is likely to be due to the greater hydro-phobicity and detergent efiect of DCA, which would be able to solubilise the lipids in the canalicular cell wall more readily. It may well explain why there have been linear relationships demonstrated between the percentage DCA in bile and (i) the mole percentage cholesterol and (ii) the cholesterol saturation index in bile. This may also explain why there is a link between the... 

In London, the Guy s Hospital group d wished to see if they could extrapolate validly from OT-treated acromegalic patients to those with sporadic gallstone disease. They also wished to study further the mechanism whereby prolongation of colonic transit might influence DCA metabolism, biliary cholesterol secretion and saturation, and therefore the risk of cholesterol gallstone formation. To study this, Thomas et developed a working hypothesis... 

Figure 13.1. Ezetimibe effects absorption of both dietary and biliary cholesterol.

CE135 Smit, M. J., H. Wolters, A. M. Temmerman, F. Kuipers, A. C. Beynen, and R. J. Vonk. Effects of dietary corn and olive oil versus coconut fat on biliary cholesterol secretion in rats. Int J Vitam Nutr Res 1994 64(1) 75-80. 

Much of the cholesterol synthesis in vertebrates takes place in the liver. A small fraction of the cholesterol made there is incorporated into the membranes of he-patocytes, but most of it is exported in one of three forms biliary cholesterol, bile acids, or cholesteryl esters. Bile acids and their salts are relatively hydrophilic cholesterol derivatives that are synthesized in the liver and aid in lipid digestion (see Fig. 17-1). Cholesteryl esters are formed in the liver through the action of acyl-CoA-cholesterol acyl transferase (ACAT). This enzyme catalyzes the transfer of a fatty acid from coenzyme A to the hydroxyl group of cholesterol (Fig. 21-38), converting the cholesterol to a more hydrophobic form. Cholesteryl esters are transported in secreted lipoprotein particles to other tissues that use cholesterol, or they are stored in the liver. 

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). 

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. 

Wilson, M.D. and Rudel, L.L. 1994. Review of cholesterol absorption with emphasis on dietary and biliary cholesterol. J. Lipid Res. 35, 943-955. 

It has been suggested that milk thistle may be beneficial in the management of hypercholesterolemia and gallstones. A small trial in humans showed a reduction in bile saturation index and biliary cholesterol concentration. The latter may reflect a reduction in liver cholesterol synthesis. To date, however, there is insufficient evidence to warrant the use of milk thistle for either of these disorders. 

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). 

PBS and gently blotted to remove blood and tissue fluids, then suspended over the lip of a small (250 pi) microcentrifuge tube and punctured with a needle to allow the bile to drain into the tube. Store frozen until assay. There is usually enough material to measure lipid composition (bile acids, cholesterol, phospholipids) with standard colorimetric kits (<1 pi needed for each assay). In addition to biliary cholesterol levels, it is important to take note of bile salt concentrations, since these are the detergents which suspend dietary lipids in micelles and deliver them to the intestinal epithelium for absorption by enterocytes. Differences in bile salt concentration alone could lead to differences in cholesterol absorption. 

Effects of drug treatment on bile composition could be beneficial or deleterious. For example, if biliary cholesterol secretion is increased in conjunction with a decrease or no change in cholesterol absorption, the overall effect may be positive. This result would suggest that reverse cholesterol transport (RCT) is increased by the treatment. This would be a very desirable effect as explained above. Increased bile salt secretion could also be beneficial for similar reasons. On the other hand, decreased biliary cholesterol or bile salt concentrations are cause for concern since either could be indicative of some degree of hepatotoxi-city and/or cholestasis. At the very least, they would indicate decreased RCT and increased CVD risk. As mentioned above, if drug treatment decreases cholesterol absorption independently of effects on biliary lipids, structural alterations of the compound may improve specificity and/or decrease its absorption so its effect is limited to the intestine. 

Others have reported similar findings (76-78) as well as an increased degradation of cholesterol in exercised mice and an increased duodenal bile flow and biliary cholesterol excretion in subjects following only 30 minutes of cycling. 

Canola oil contains a relatively high level of phytosterols (892 mg/100 g), about twice the level in soybean oil or sunflower oil (436 and 496 mg/100 g respectively) (Table 8). p-Sitosterol accounts for about 50%, campesterol 35%, and brassicasterol 14% of the total phytosterols in canola oil. Canola oil is the only common vegetable oil that contains brassicasterol. Plant sterols have been reported to lower plasma cholesterol level (107) by inhibiting the absorption of dietary cholesterol and the reabsorption of biliary cholesterol (108). 

Baggio, G., Pagnan, A., Muraca, M., Martini, S., Opportune, A., Bonanome, A., Ambrosio, G., Ferrari, S., Guarini, R, Piccolo, D., Manzato, E., Corrocher, R., and Crepaldi, G. (1988). Olive-oil-enriched diet Effect on serum lipoprotein levels and biliary cholesterol saturation. Am. J. Clin. Nutr. 47, 960-964. 

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