LYCOS RETRIEVER 
Bile
built 236 days ago
Bile acid levels in the enterohepatic circulation are under tight negative feedback control, mainly achieved through transcriptional control of bile acid synthetic enzymes involving farnesoid X receptor (FXR) (6) (Fig. 2). Liver X receptor (LXR) is a master regulator of a feed-forward mechanism that helps to maintain cholesterol homeostasis. On activation by oxysterols, LXR forms heterodimers with the retinoid X receptor, which induce the expression of several genes that facilitate intestinal sterol excretion and reverse cholesterol transport. In the liver, 7-hydroxylation of cholesterol is regulated in an LXR-dependent manner, thereby increasing bile acid synthesis. However, humans do not respond with upregulation of CYP7A1 in response to excess dietary cholesterol, probably attributable to the absence of an LXR-responsive element in the CYP7A1 promoter (1).
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Bile is a complex biochemical mixture, made continuously by the liver — 500-1000 ml/day passing down into the duodenum via the bile duct. There is a diversion in this journey: a small 50 ml sac — the gall bladder — fills with bile from the liver, and, by absorbing water across its walls, concentrates bile 5-6-fold. Shortly after a meal the gall bladder contracts and empties, and the concentrated bile is added to the partially digested food (‘chyles insipid tide’ in Prior's poem above). Bile has two broad functions: it plays a digestive role in the breakdown and absorption of fat, and it excretes substances from blood which cannot be excreted by the kidneys. These substances are usually fat soluble; they may be produced by the body, or come from outside, like drugs. In composition, bile is 97% water; its other major components are bile salts, cholesterol, phospholipids, bile pigments, and electrolytes (minerals).
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Bile acid sequestrants have modest LDL cholesterol lowering effects. Low doses (for example 8 gram/day of Cholestyramine) can lower LDL cholesterol by 10%-15 %. But even high doses (24 gram/day of cholestyramine) can only lower LDL cholesterol by approximately 25%. Therefore, bile acid sequestrants used alone are not as effective as statins in lowering LDL cholesterol.
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Bile acids work by altering the chemistry of cholesterol processing. Under normal circumstances, the liver takes cholesterol out of the blood to make bile, which is used in the intestines during the digestive process. Most of this bile is eventually returned to the liver. Bile acid resins block the recycling of bile acids in the intestine. To replace the lost bile acids, the liver is forced to remove more cholesterol from the blood to manufacture more bile. Bile acid resins are usually prescribed in powder form (which is mixed with liquid) or in a chewable bar.
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Bile acids, amphipathic detergent-like molecules synthesized from cholesterol, are highly conserved by means of enterohepatic circulation. They participate in the generation of bile flow and biliary lipid secretion and ... promote absorption of fat-soluble vitamins and lipids. Conversion of cholesterol to bile acids represents a quantitatively important route to eliminate cholesterol from the body. Regulation of bile acid synthesis involves a complex and interrelated group of transcription regulators that link bile acid synthesis to cholesterol and fatty acid metabolism. Targeting key steps of bile acid synthetic pathways as well as the metabolic network that maintains homeostatic levels of lipids should provide exciting novel opportunities for the treatment of cardiovascular and liver diseases.
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Bile is produced by hepatocytes in the liver, draining through the many bile ducts that penetrate the liver. During this process, the epithelial cells add a watery solution that is rich in bicarbonates that dilutes and increases alkalinity of the solution. Bile then flows into the common hepatic duct, which joins with the cystic duct from the gallbladder to form the common bile duct. The common bile duct in turn joins with the pancreatic duct to empty into the duodenum. If the sphincter of Oddi is closed, bile is prevented from draining into the intestine and instead flows into the gall bladder, where it is stored and concentrated to up to five times its original potency between meals. This concentration occurs through the absorption of water and small electrolytes, while retaining all the original organic molecules.
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