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Received Dec 8, 2017; Accepted Feb 7, 2018
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1. Introduction
Bile acids (BAs) exert an essential role in the control of lipid and cholesterol homeostasis and constitute the major endogenous component of the human bile [1]. Their formation from cholesterol in the liver accounts for 90% of cholesterol catabolism. The hepatic BA synthesizing pathways lead to formation of the primary chenodeoxycholic (CDCA) and cholic (CA) acids which are, in part, conjugated with taurine and glycine to form amidated acids [1]. Conjugated and unconjugated BAs are stored in the gallbladder and secreted in the intestine, where they act as natural detergents to facilitate the absorption of dietary lipids, liposoluble vitamins, and cholesterol [1]. A significant proportion of CDCA and CA can be deconjugated and converted in the respective secondary lithocholic (LCA) and deoxycholic (DCA) acids by resident bacteria from the large intestine [1]. Both primary and secondary acids are reabsorbed and return to the liver via the portal circulation. Back in the liver, LCA and CDCA sustain additional biotransformation into 6α-hydroxylated hyodeoxycholic (HDCA) and hyocholic acids (HCA), respectively [1].
Their detergent properties render BAs hepatotoxic at high concentration [2]. Their retention leads to liver dysfunction, as observed when bile secretion is impaired, a situation called cholestasis [3]. BA accumulation in hepatocytes can cause apoptosis [4] or necrosis [5], with unequal contribution of both types of cell damage to liver injury [6]. To overcome these deleterious effects, the liver has developed self-protective mechanisms based on the regulation of BA synthesis, metabolism, and excretion. Accordingly, when BAs accumulate in liver cells, genes controlling their synthesis, such as the cytochrome P450 (CYP)7A1 and 27A1, are repressed [7] leading to an increased formation of the less toxic glyco- and tauro-conjugated BAs [8]. While canalicular BA is exported by the bile salt export pump (BSEP) and multidrug resistance protein (MRP) 2 remains unchanged [9], the elimination of accumulating BAs from the liver is reinforced through the activation of an alternative basolateral transport system involving the organic solute transporter alpha/beta (OSTα/β) and MRP3 and 4 proteins...