Lipid absorption bile acids

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. 

Fat-soluble vitamins require the simultaneous presence of lipids and bile acids for their absorption. In order to be transported to the liver, they are bound to lipoproteins of the chylomicrons. Fat-soluble vitamins are stored in the liver or fatty tissue, often in large amounts and for prolonged periods of time. From there they become available to the intermediary metabolism for complex tasks. Vitamins A and D are secreted from the liver cells by means of carrier proteins. By undergoing biotransformation, fat-soluble vitamins become meta-bolically inactive as well as water-soluble and are thus capable of being excreted, (s. tab. 3.13)... 

The regulation of bile acid metabolism is a major function of the liver. Alterations in bile acid metabolism are usually a reflection of liver dysfunction. Cholesterol homeostasis is in large part maintained by the conversion of cholesterol to bile acids and subsequent regulation of bile add metabolism. Bile acids themselves provide surface-active detergent molecules that facilitate both hepatic excretion of cholesterol and solubilization of lipids for intestinal absorption. Bile acid homeostasis requires normal terminal ileum function to absorb bile adds for recirculation (enterohepatic circulation). Alterations in hepatic bile acid synthesis, intracellular metabolism, excretion, intestinal absorption, or plasma extraction are reflected in derangements in bile add metabolism. 

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). 

In addition to the passive diffusional processes over lipid membranes or between cells, substances can be transferred through the lipid phase of biological membranes through specialized systems, i.e., active transport and facilitated diffusion. Until recently, the active transport component has been discussed only for nutrients or endogenous substances (e.g., amino acids, sugars, bile acids, small peptides), and seemed not to play any major role in the absorption of pharmaceuticals. However, sufficient evidence has now been gathered to recognize the involvement of transporters in the disposition of pharmaceuticals in the body [50, 127]. 

In addition to more rapid absorption of lipids in animals fed casein, another mechanism that may be operative is decreased clearance of circulating lipids. Rabbits fed a casein-based semipurified diet excreted significantly less cholesterol but more bile acids in their feces than animals fed a commercial diet (18). The total sterol excretion in feces of the animals fed the casein diet was half that of the rabbits fed the stock diet. Huff and Carroll (19) found that rabbits fed soy protein had a much faster turnover rate of cholesterol and a significantly reduced rapidly exchangeable cholesterol pool compared with rabbits fed casein. Similar studies performed in our laboratory revealed that the mean transit time for cholesterol was 18.4 days in rabbits fed soy protein, 36.8 days in rabbits fed casein, 33.7 days in rabbits fed soy plus lysine, and 36.3 days in rabbits fed casein plus arginine. These data suggest that addition of lysine to soy protein... 

Bile helps in the digestion and absorption of fats. Its constituent bile acids (BAs) have detergent properties, and some can be carcinogenic. BAs can act as signalling molecules, entering the nuclei and reacting with the nuclear receptors and this could enhance or reduce BA synthesis. In this way, they control their own levels as well as those of their precursor, cholesterol. This controls cholesterol homeostasis and BA and lipid synthesis. 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

Faecal bile-acid content was increased in colestimide-supplemented mice consistent with the mode of action of the BAS. In addition, faecal lipid content was raised in treated animals, suggesting reduced lipid absorption, presumably via the lowering of duodenal bile-acid concentration. 

Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of -amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs. 

Impairment of bile acid absorption and consequent loss of these acids via excretion presumably causes an increase in hepatic conversion of cholesterol to bile acids. This conversion lowers serum cholesterol, particularly when serum contains high levels of cholesterol derived from dietary intake. However, when fed with a cholesterol-free diet, 10% pectin supplementation stimulated a 3-fold increase in cholesterol biosynthesis (77). Biosynthesis of phospholipids and triglycerides also increased significantly hence, it was suggested that these increases occurred in response to diminished fat absorption occasioned by pectin intake. This compensatory biosynthesis of cholesterol and lipids may account for pectin s inability (in most cases) to lower serum cholesterol levels in animals fed cholesterol-free diets. 

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. 

Despite these variables, it appears that the primary attribute of soluble fibers that inhibit cholesterol absorption is the ability to form a viscous matrix when hydrated. Many water-soluble fibers become viscous in the small intestine (Eastwood and Morris, 1992). It is believed that increased viscosity impedes the movement of cholesterol, bile acids, and other lipids and hinders micelle formation, thus reducing cholesterol absorption and promoting cholesterol excretion from the body. Consumption of viscous fibers was shown to increase the thickness of the unstirred water layer in humans (Flourie et al., 1984 Johnson and Gee, 1981) and reduce the amount of cholesterol appearing in the lymph of cannulated rats (Ikeda et al., 1989b Vahouny et al., 1988). Turley et al. (1991, 1994) reported that... 

The bile salts form the edge of the micelle and also appear, in fewer numbers, dispersed throughout the inside of the micelle. The lipids exist in a bilayer on the inside of the disc. Bile acids are important for fatty acid absorption. Fat-soluble vitamins (A, D, E, and K) absolutely require bile acids for absorption. 

Cholesterol also serves as a precursor to other important molecules. Bile acids aid in lipid absorption during digestion. Steroid hormones all derive from cholesterol, including the adrenal hormones that maintain fluid balance Vitamin D, which is an important regulator of calcium status and the male and female sex hormones. Although humans wouldn t survive in one sense or another without cholesterol metabolites, cholesterol brings with it some well-known side effects. Doctors find cholesterol derivatives, being essentially insoluble in water, in the deposits (plaque) that characterize diseased arteries. 

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