Abstract
Undisturbed bile secretion is vital for normal liver function. Bile acids are the major solutes in bile. The primary bile acids, chenodeoxycholic acid (dihydroxylated) and cholic acid (trihydroxylated), are the predominant species and are synthesized from cholesterol. Their pKa values are about 6 and 5, respectively. After amidation at position C24 with glycine or taurine, the pKa value drops to approximately 4 for glycine conjugates and to below 2 for taurine conjugates [1]. Due to their relatively high pKa values, unconjugated bile acids are protonated (i.e. uncharged) to a significant extent at physiological pH, and as such, may cross plasma membranes by diffusion. In contrast, because of their lower pKa values, conjugated bile acids are present predominantly in the anionic form, precluding them from diffusion across plasma membranes. Therefore, conjugated bile acids will be called bile salts. As a consequence of their detergent properties, bile salts promote aggregation of phospholipids and cholesterol within mixed micelles in bile and thereby provide a vehicle for the excretion of hydrophobic compounds via bile. Canalicular secretion of bile constituents involves the coordinated action of an array of different transport systems [2]. Bile salts are then secreted via the bile duct into the duodenum where they promote absorption of dietary fats and lipid-soluble vitamins. Bile salts are almost quantitatively reabsorbed in the small intestine and transported back to the liver via portal blood for uptake into hepatocytes and resecretion into bile for enterohepatic circulation [3]. Canalicular bile salt secretion is mediated by the canalicular bile salt export pump (Bsep/BSEP, Abcb11 (rodents), ABCB11 (human)), which constitutes a key driving force in enterohepatic circulation. Impairment of canalicular secretion of major bile constituents (e.g. bile salts, phospholipids) leads to a reduction in bile flow or cholestasis [4]. Cholestasis may be acquired, e.g. induced by sepsis, adverse drug reactions, pregnancy, or it may be inherited. Inherited forms of cholestasis or progressive familial intrahepatic cholestasis (PFIC) are subdivided into three forms [5,6]: PFIC1 (known as Byler's disease) patients have low γ-glutamyltransferase and high bile salt levels in serum and a secondary bile salt transport defect; PFIC2 (Byler's syndrome) patients also have low γ-glutamyltransferase and high bile salt levels in serum and a primary bile salt transport defect; PFIC3 patients have high γ-glutamyltransferase and moderate bile salt levels and a phospholipid transport defect. A gene locus for PFIC1 was mapped to 18q21–q22, while the locus for PFIC2 maps to chromosome 2q24 [5]. The BSEP gene codes for the canalicular bile salt export pump BSEP [7]. The locus for PFIC3 maps to chromosome 7q21. Its gene product codes for MDR3 (ABCB4), a phosphatidylcholine translocator [8]. While the biochemical function of the gene products causing PFIC2 and PCIC3 is well understood, the function of the gene causing PFIC1 has remained enigmatic so far. In contrast to PFIC1, which ultimately can lead to liver failure, benign recurrent intrahepatic cholestasis (BRIC) is an inherited form of cholestasis with recurrent episodes of intrahepatic cholestasis, which resolve spontaneously. High-resolution mapping of loci for PFIC1 and BRIC lead to the identification of a common mutated gene for both diseases: FIC1 [9].
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