Cholesterol bile salts from

Bile. The liver forms a thin secretion (bile) that is stored in the gallbladder after water and salts have been extracted from it. From the gallbladder, it is released into the duodenum. The most important constituents of bile are water and inorganic salts, bile acids and bile salts (see p. 314), phospholipids, bile pigments, and cholesterol. Bile salts, together with phospholipids, emulsify insoluble food lipids and activate the lipases. Without bile, fats would be inadequately cleaved, if at all, resulting in fatty stool (steatorrhea). Resorption of fat-soluble vitamins would also be affected. 

Ophthalmic, transmucosal, and transdermal products will be the most sensitive to the strength of binding. These routes of administration experience minimal dilution. However, this may not be a signiLcant concern because the drug typically can also be displaced from the CD cavity at the delivery site by competing lipophiles at the delivery site, such as triglycerides, cholesterol, bile salts, and other hydrophobic compounds, which are often in much higher concentrations (Thompson, 1997). 

A special consideration in the digestion of fats is that they are not water soluble and cannot be placed in aqueous solution along with the water-soluble lipase digestive enzymes. However, intimate contact is obtained by emulsification of fats through the action of bile salts from glycocholic and taurocholic acids produced from cholesterol in the liver ... 

Figure 19.1 Biosynthesis of bile salts from cholesterol. Mit, mitochondria ER, endoplasmic reticulum.

The digestion and absorption of dietary lipid can be completed only in the presence of adequate amounts of bile salts that are synthesized in the liver and pass, via the bile duct, into the duodenum and thence into the jejunum. Reabsorption of the bile salt micelles occurs in the ileum, from which a large proportion return via the blood to the liver. The bile ducts carry bile salts from the liver to the gallbladder, where they are stored excreted (excess) cholesterol is dissolved in the bile salt micelles. Overall, 90 percent of the bile salts involved in absorption of lipid in the jejunum are recycled, in a process called the enterohepatic circulation, and 10 percent are lost in the feces. Replacement of this amount necessitates conversion from cholesterol. Thus, de novo synthesis of cholesterol itself plays an important part in maintaining the supply of bile salts. 

Vital for membrane formation Preeursor of hormones too Bile salts from its oxidation Cholesterol is good for you Atheroma eareinoma ... 

In addition to bile salts, which facilitate the digestion of lipids, five major classes of steroid hormones are derived from cholesterol progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens. Hydroxylations by P450 monooxygenases that use NADPH and O2 play an important role in the synthesis of steroid hormones and bile salts from... 

Fig. 7, Phase diagram showing the physical state of all possible combinations of cholesterol, bile salts, and lecithin (expressed as mole percent) in aqueous solutions. The line AB represents the maximum amount of cholesterol, according to Admirand and Small (A2), which can be dissolved by any mixture of bile salts and lecithin. [From ref. (A2). Reproduced from The Journal of Clinical Investigation, 1968, 47, by copyright permission ofThe American Society for Clinical Investigation.]...

One idea for treating hypercholesterolemia is to decrease the reabsorption of bile salts from the intestinal contents by ingesting anion-exchange resin that retains the bile salts in the intestinal lumen (Sec. 12.2). The liver, however, responds by synthesizing more cholesterol so the treatment is not as effective as might have been anticipated. 

FIGURE 25.41 Cholic acid, a bile salt, is synthesized from cholesterol via 7o -hydroxy-cholesterol. Conjugation with taurine or glycine produces taurocholic acid and glycocholic acid, respectively. Taurocholate and glycocholate are freely water-soluble and are highly effective detergents. 

CHOLESTEROL IS EXCRETED FROM THE BODY IN THE BILE AS CHOLESTEROL OR BILE ACIDS (SALTS)... 

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98—99% are returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26—6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the small pool of bile acids (about 3-5 g) is cycled through the intestine six to ten times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls. 

Irrespective of the physical form of the carotenoid in the plant tissue it needs to be dissolved directly into the bulk lipid phase (emulsion) and then into the mixed micelles formed from the emulsion droplets by the action of lipases and bile. Alternatively it can dissolve directly into the mixed micelles. The micelles then diffuse through the unstirred water layer covering the brush border of the enterocytes and dissociate, and the components are then absorbed. Although lipid absorption at this point is essentially complete, bile salts and sterols (cholesterol) may not be fully absorbed and are not wholly recovered more distally, some being lost into the large intestine. It is not known whether carotenoids incorporated into mixed micelles are fully or only partially absorbed. 

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

The overall metabolism of vitamin A in the body is regulated by esterases. Dietary retinyl esters are hydrolyzed enzymatically in the intestinal lumen, and free retinol enters the enterocyte, where it is re-esterified. The resulting esters are then packed into chylomicrons delivered via the lymphatic system to the liver, where they are again hydrolyzed and re-esterified for storage. Prior to mobilization from the liver, the retinyl esters are hydrolyzed, and free retinol is complexed with the retinol-binding protein for secretion from the liver [101]. Different esterases are involved in this sequence. Hydrolysis of dietary retinyl esters in the lumen is catalyzed by pancreatic sterol esterase (steryl-ester acylhydrolase, cholesterol esterase, EC 3.1.1.13) [102], A bile salt independent retinyl-palmitate esterase (EC 3.1.1.21) located in the liver cell plasma hydrolyzes retinyl esters delivered to the liver by chylomicrons. Another neutral retinyl ester hydrolase has been found in the nuclear and cytosolic fractions of liver homogenates. This enzyme is stimulated by bile salts and has properties nearly identical to those observed for... 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

Figure 2.2 Secretion of bile acids and biliary components. Bile acids (BA) cross the hepatocyte bound to 3a-hydroxysteroid dehydrogenase and are exported into the canaliculus by the bile-salt export protein (BSEP). Phosphatidylcholine (PC) from the inner leaflet of the apical membrane is flipped to the outer layer and interacts with bile acids secreted by BSEP. BA, PC, together with cholesterol from the membrane form mixed micelles that are not toxic to epithelial membranes of the biliary tree. Aquaporins (AQP) secrete water into bile.

Bile is an important product released by the hepatocytes. It promotes the digestion of fats from food by emulsifying them in the small intestine (see p. 2770). The emulsifying components of bile, apart from phospholipids, mainly consist of bile acids and bile salts (see below). The bile also contains free cholesterol, which is excreted in this way (see p. 312). 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

In comparison, addition of organic molecules such as methanol or ethanol decreases the magnitude of y of water from 72 mN/m rather slowly. The value of y decreases from 72 to 22 mN/m in pure ethanol. In comparison, the value of y of surfactant solutions decreases to 30 mN/m with surfactant concentration around millimoles per liter (range of 1 to 10 g/L). Soaps have been used by humans for many centuries. In biology, one finds a whole range of amphiphile molecules (bile salts, fatty acids, cholesterol and other related molecules, phospholipids). 

HDL particles extract cholesterol from peripheral membranes and, after esterification of cholesterol to a fatty acid, the cholesteryl esters are delivered to the liver (to make bile salts) or steroidogenic tissues (precursor of steroids). 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

Cholesterol is a soft waxy substance that is a steroidal alcohol or sterol. It is the most abundant steroid in the human body and is a component of every cell. Cholesterol is essential to life and most animals and many plants contain this compound. Cholesterol biosynthesis occurs primarily in the liver, but it may be produced in other organs. A number of other substances are synthesized from cholesterol including vitamin D, steroid hormones (including the sex hormones), and bile salts. Cholesterol resides mainly in cell membranes. 

Bile is an aqueous solution of bile salts, inorganic salts, bile pigments, fats, cholesterol, and others. The physiology of bile secretion is not simple, as it involves the active excretion of organic solutes from the blood to the bile. Bile is collected directly from the liver cells through separate channels, without being mixed with blood. The liver cell membrane incorporates extremely fine passages that permit bile secretion. 

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