Biliary systems are exposed to bile rich in lipids and bile salts

Biliary systems are exposed to bile rich in lipids and bile salts under a physiological circumstance. Bile salts are strong detergents and certain lipid molecules such as lysophosphatidylcholine (lysoPC), oxidized fatty acids, are also having

a detergent potential. Accordingly, there must be a protective system against such cytotoxic constituents in bile. In principle, biliary carcinogenesis is considered to be related to chronic biliary inflammation and click here pancreatobiliary reflux,[26] and thus, the degradation of biliary lipids, a nutritional factor, is focused on in the light of cytotoxicity and cytoprotection of biliary systems under a certain condition of chronic biliary disorders, such as pancreaticobiliary

maljunction. Bile consists of cholesterol, phospholipids, and bile salts. Bile salts are composed of various species as well as phospholipids. Our previous reports indicate that hydrophobic bile salts induce cholangiocyte apoptosis through the oxidative stress-mediated mechanism.[27] Cholangiocyte has an absorption system of bile salts (apical sodium-dependent bile salt transporter) and the excess bile salts, which induce apoptosis through death signals, are eliminated through a membrane transporter (multidrug resistance transporter-associated protein 3) in a rodent model, and those molecules are regulated by a nuclear receptor (farnesoid X receptor) as summarized Rapamycin order in Figure 6.[28, 29] The regulatory system for bile salt trafficking is mediated by nuclear receptors affecting various bile salt transporters expression. In this scenario, the fact that UDCA, a hydrophilic bile salt, and phospholipids such as PC play a role as the rescue system is of pathophysiological importance.[30, 31] Similar phenomenon is evident in the gallbladder.[32] Thus, a disruption

of these systems is very likely to cause serious biliary damages. There is an important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. LysoPC, a derivative of PC hydrolysis by PLA2, is a highly abundant bioactive lipid mediator present in medchemexpress circulation as well as in bile. LysoPC and PLA2 are significantly increased in bile of the patients with pancreaticobiliary maljunction or intrahepatic cholelithiasis, both of which are considered to be major risk factors for biliary tract cancers with undefined etiology. Biliary epithelial cells are continuously exposed to bile, and an increase of biliary lysoPC is suggested to induce biliary cell damages and the subsequent carcinogenesis. In our previous study investigating the influence of lysoPC on HuCCT-1, a human cholangiocellular carcinoma cell line, LysoPC exhibited significant cytotoxicity with induction of apoptosis (unpublished data).

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