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INTRODUCTION

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Bile (gall) is a greenish yellow secretion produced by hepatocytes and actively pumped into the bile duct tree to be passed to the gallbladder, where it is concentrated, stored, and subsequently released into the duodenum under hormonal and neural control. Bile is a mildly alkaline liquid composed of electrolytes, bile acids and salts, cholesterol, phospholipids, heme breakdown products such a bilirubin and biliverdin that provide color, and water. Bile acids are derived from cholesterol and act as detergents important in keeping cholesterol in solution in bile and in the digestion and absorption of fats and fat-soluble vitamins in the intestine. The detergent properties of bile acids are determined by the number and orientation of the hydroxyl groups and the presence or absence of an amino acid moiety. The conversion of cholesterol to bile acids and the secretion of cholesterol into bile constitute a major route for the elimination of excess cholesterol. Bile acids have also been identified as important transcriptional activators as natural ligands for transcription factor farnesoid X receptor (FXR; also known as bile acid receptor or nuclear receptor subfamily 1 group H member 4) and by modulating energy metabolism through signaling via the membrane-bound, G-protein–coupled bile acid receptor 1 (Gpbar-1, also known as TGR5). The expression of a number of genes that encode proteins involved in bile acid synthesis, transport, and metabolism is directly controlled by bile acids via activation of FXR and Gpbar-1, as are other genes involved in lipid and glucose metabolism. Hepatic FXR inhibits bile acid synthesis by a feedback mechanism requiring small heterodimer partner (SHP)-mediated CYP7A1 repression. SHP, an unusual nuclear receptor lacking a DNA-binding domain, exhibits transcriptional repression upon dimerization with several transcription factors. Additionally, ileal FXR induces FGF19 secretion into the portal circulation in response to bile acid absorption, which in turn represses hepatic CYP7A1 through FGFR4-mediated signaling, a pathway requiring the interaction of FGFR4 and the cell surface single-pass transmembrane protein β-Klotho. Activation of FXR interferes with glycolytic glucose metabolism, directing glucose to glycogen storage. FXR activation also represses de novo lipogenesis via inhibition of lipogenic enzymes such as acetyl-CoA carboxylase-1 and fatty acid synthase, leading to a reduced hepatic very-low-density lipoprotein output. Hence, bile acids act as metabolic integrators that are particularly active postprandially, promoting glycogen accumulation and inhibiting lipid synthesis.

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Individuals with disorders of bile acid synthesis may exhibit liver disease due to impaired bile secretion (cholestasis), along with symptoms of fat-soluble vitamin deficiency, gallstones, steatorrhea due to fat malabsorption, and the accumulation of cholesterol in tissues leading to cutaneous xanthomata and atherosclerosis. The major bile acids produced in the liver are the taurine and glycine conjugates (amidates) of chenodeoxycholic acid (CDCA) and cholic acid (CA), the 2 primary bile acids. CA is a trihydroxy-bile acid with hydroxyl groups at positions C-3, C-7, and C-12, whereas CDCA is a dihydroxy-bile acid with hydroxyl groups at C-3 and C-7. Secretion of these conjugated bile acids into the canaliculi via ...

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