Bile acids biliary secretion

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.

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. 

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... 

The liver secretes about 1 L of bile daily. Bile flow and composition depend on the secretory activity of the hepatic cells that line the biliary canaliculi. As the bile flows through the biliary system of ducts, its composition can be modified in the ductules and ducts by the processes of reabsorption and secretion, especially of electrolytes and water. For example, osmotically active compounds, including bile acids, transported into the bile promote the passive movement of fluid into the duct lumen. In the gallbladder, composition of the bile is modified further through reabsorptive processes. 

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. 

A greater amount of biliary solids and pronouncedly higher rate of secretion of bile acids were caused by various spices including fennel, probably contributing to the digestive stimulant action of the test spices (Patel and Srinivasan, 2000). 

Disturbed secretion of bile acids Impaired fat solubilization, decreased formation of micelles Primary biliary cirrhosis Primary sclerosing cholangitis... 

The rate-limiting step for cholesterol synthesis is the production of mevalonate from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by the enzyme HMG-CoA reductase. Cholesterol synthesised in the hep-atocyte can be further metabolised by lecithin cholesterol acyl transferase (LCAT) to cholesterol ester, which is packaged into lipoproteins and secreted into the bloodstream. Alternatively, it can be excreted via the biliary system either as a neutral lipid or following conversion to bile acids. 

The body s bile acid pool (2-5 g, 5-10 mmol) is held constant by the balance between the rates of synthesis and excretion. This pool is brought into circulation 3-10 times/day by biliary secretion of the bile acids into the intestine at a rate of 12-24 g/day (30-60 mmol/ day). As a general rule, the pool circulates 2(-3) times per meal. Approximately 95% of the intestinal bile acids are reabsorbed. The hourly uptake of bile acids by the liver is in the order of 450 gmol (180 mg). 

Biochemically, a change in structure relating to the mucopolysaccharides (neuraminic add ) and monohydroxy bile acids probably accounts for the formation of biliary thrombi. Some of the under-hydroxylated bile salts appear in crystalline form the bile becomes increasingly viscous and its flow is impeded. This defect in the excretion of bile salts culminates in dysfunctions in the secretion of bilirubin, which is why bilirubin is regurgitated into the blood. The bile which accmnulates in the bile ducts ultimately becomes mucous and white because of the reabsorption of bile pigments by the epitheha of the small bile ducts. 

Cholesterol is presented to the intestinal wall from three sources the diet, bile and intestinal secretions, and cells. Animal products—especially meat, egg yolk, seafood, and whole-fat dairy products— provide the bulk of dietary cholesterol. Although cholesterol intake varies considerably according to the dietary intake of animal products, the average American diet is estimated to contain approximately 300 to 450 mg of cholesterol per day. A similar amount of cholesterol is present in the gut from biliary secretion and the turnover of mucosal cells. Practically ail cholesterol in the intestine is present in the unesterified (free) form. Esterified cholesterol in the diet is rapidly hydrolyzed in the intestine to free cholesterol and free fatty acids by cholesterol esterases secreted from the pancreas and small intestine. 

Bile formation occurs by processes that are not hilly defined. It takes place in canaliculi, minute passages lined by specialized modihcations of the hepatocyte membrane, that ultimately unite to form bile ductules. Hepatic bile contains 5% to 15% total solids, the major component of which is bile acids. The increase in biliary water and electrolyte excretion caused by this osmotic effect represents the bile acid-dependent fraction of bile flow. Even with severe depletion of the circulating bile acid pool, as is seen with bile duct diversion, some bile flow continues. The active transport of sodium and of glutathione and bicarbonate is mediated by Na-K-ATPase, which is responsible for the bile acid-independent flow of bile (up to 40% of total flow). Hormones such as secretin increase bile flow by stimulating secretion of sodium, bicarbonate, and chloride. Hormone-dependent flow accounts for 20% to 25% of the total. 

Alvaro D, Angelico M, Cantafora A, Dibiase A, Desantis A, Bracci F, Minervini G, Corradini SG, Attili AF and Capocaccia L. Biliary-Secretion of Phosphatidylcholine and its Molecular-iSpecies in Cholecystectomized T-Tube Patients— Effects of Bile-Acid Hydrophilicity. Biochem Med Metab Biol 1986 36 125— 135. 

Routes other than biliary secretion of triCB MAP metabolites must also be considered in formation of triCB-methylsulfones from triCB mercapturlc acid because rats with cannulated bile ducts, dosed either with triCB (72) or triCB mercapturate (40), also had... 

Bile acids, which have been taken up by the liver, are transported across the hepatocyte and secreted into the bile canaliculus. Newly synthesized bile acids, in a small amount just sufftcient to balance the fraction lost by fecal excretion, join recycled bile acids for biliary secretion. Intracellular bile acid transport may be mediated by carrier proteins (B24, S42). The detailed mechanism of biliary secretion of bile acids and other organic anions into the bile canaliculus is not yet clear (B24). Possible mechanisms include vectorial vesicular transport, fticilitated diflusion, or an energy-requiring carrier-mediated transport process (B24). 

TNAP is expressed in human hepatocytes, and bile acids increase its activity [93] and secretion in the bile [94]. TNAP in rat hepatocytes is predominantly localized in the bile canalicular domain of the plasma membrane [95, 96], but can be addressed to the baso-lateral membrane in the presence of high levels of bile acid [97]. In contrast, mouse hepatocytes do not express TNAP [98]. In humans, liver TNAP may be expressed both at the sinusoidal and biliary pole of the hepatocyte. This explains why a significant proportion of TNAP activity in the circulation of healthy individuals originates from the liver. TNAP serum levels are of major clinical relevance as a marker of cholestasis. AP levels increase due to retrograde reflux of biliary alkaline phosphatase, enhanced hepatic synthesis and enzyme release into the serum, and induction of the intestinal alkaline phosphatase form [94, 99, 100]. 

Control of these mechanisms occurs at several levels. The uptake of VLDL remnants and LDL by the apo B/E receptor has been shown to be Unked to the excretion of biliary UC and bile acids [122], whereas the formation of intracellular CE by the ACAT reaction seems to be inversely proportionate to the excretion of the same bile components [123]. The uptake of chylomicron remnants does not seem to be related to bile formation and excretion. Instead, when large amounts of remnant CE enter hepatocytes, as is seen in some species in diet-induced hypercholesterolemia, the CE is hydrolyzed within lysosomes, then reformed by the ACAT reaction and recirculated in the plasma as VLDL CE. Less is known about the control of LCAT secretion by the Ever. In rats and in humans the activity of LCAT in the plasma seems to be hnked not only to the transport of cholesterol, but also to the transport of essential fatty acids [124]. 

The hydrolysis of bile acid conjugates is probably the initial reaction catalyzed by intestinal bacteria. Therefore, primarily free bile acids are isolated from the feces of man and animals [1-5]. The bulk of the free bile acids in feces of man is deoxycholic acid and lithocholic acid which are generated by the 7 -dehydroxylation of cholic acid and chenodeoxycholic acid, respectively. A portion of fecal acids is absorbed from the intestinal tract, returned to the liver where they are conjugated and again secreted via biliary bile. Therefore, the final composition of biliary bile acids is the result of a complex interaction between liver enzymes and enzymes in intestinal bacteria. 

A FIGURE 18-11 Major transport proteins in the liver and intestines taking part in the enterohepatic circulation of biliary lipids. The secretion of bile components and recycling of bile acids are mediated by a diverse array of transport proteins in liver cells (hepatocytes) and intestinal epithelial cells. Both of these polarized cell types import lipids across one surface and export them across the opposite surface. Step D Hepatocytes export lipids across their apical membranes into the bile by using three ATP-dependent ABC proteins ABCB4 (phospholipids), ABCB11 (bile acids), and ABCG5/8 (sterols). Step B. Intestinal epithelial cells import bile components and dietary lipids from the... 

Because the amount of dietary cholesterol is normally low, a substantial fraction of the cholesterol in the intestinal lumen comes from the biliary cholesterol secreted by the liver. ABCG5/8 also is expressed in the apical membrane of intestinal epithelial cells, where it helps control the amounts of cholesterol and plant-derived sterols absorbed apparently by pumping excess or unwanted absorbed sterols out of the epithelial cells back into the lumen (see Figure 18-11, step 5]). Partly as a result of this activity, only about 1 percent of dietary plant sterols, which are not metabolically useful to mammals, enter the bloodstream. Unabsorbed bile acids (normally <5 percent of the luminal bile acids) and unabsorbed cholesterol and plant sterols are eventually excreted in the feces. 

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