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PO3-5-14

Diet-induced mislocalization of the ATP-binding cassette transporters is involved in the development of cholesterol crystal in bile from gallstone disease model mouse

[Speaker] Yasuhiro Yamazaki:1
[Co-author] Chiaki Ono:1, Kazuki Saegusa:1, Ayumi Ohnishi:1, Junko Kurokawa:1
1:School of Pharma Science, University of Shizuoka, Department of Bio-informational pharmacology, Japan

 The cholesterol gallstone disease (CGD) is one of the most common and expensive digestive diseases. The pathophysiological conditions that predispose to CGD are the formation of lithogenic bile evoked by cholesterol supersaturation or relative increase concentration of cholesterol in bile. Excretion of bile lipids is mediated by the ATP-binding cassette (ABC) transporters in liver bile cnalaiculi, the functional changes of these transporters are possible to be involved in the pathogenesis of the CGD. Here, we investigated the changes in the expression of these transporters in mouse model for gallstone disease.
 Group of mice were given the lithogenic-diet (LD) for 0, 2, 4, 7, or 14 days, then the mRNA levels of ABC transporters in liver were determined. The lipid components of bile were also analyzed. LD consumption induced marked increase of the mRNA levels of Abcg5 and Abcg8, which secrete cholesterol into bile, and coincidently elevation of cholesterol concentration in bile at 2 days after feeding. Whereas the concentration of bile salts in bile was decreased, although the mRNA level of Abcb11, which excrete bile salts into bile, was slightly increased at 7 days after feeding. Immunohistochemical analyses revealed that 7 days feeding of LD enhanced the canalicular localization of Abcg5, but inhibited that of Abcb11, indicating the alteration of the distribution of transporters may evoke the inappropriate secretion of bile constituents. Since conventional protein kinase C (cPKC) are reported to be involved in the internalization of Abcb11 in hepatocyte, we examined the participation of PKCa in this diet-induced event. As a result, 7 days feeding of LD induced canalicular localization of PKCa in mouse liver. These results suggest that the lithogenic diet perturbed the canalicular localization of ABC transporters at least in part by PKCa signaling in hepatocytes, which led to the supersaturation of cholesterol in bile.

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