title: Aberrant activation of atypical protein kinase C in carbon tetrachloride-induced oxidative stress provokes a disturbance of cell polarity and sealing of bile canalicular lumen.
abstract: Polarized hepatocytes contain tight junctions (TJs), which are among the most important junctions for sealing the bile canalicular lumen from the sinusoidal space. Alterations in TJs are implicated in chronic cholestatic liver diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis, which have lipid peroxidation marker elevations or antioxidant vitamin decreases. However, the effect of oxidative stress on hepatocyte polarity or liver morphology is unknown. We found that carbon tetrachloride (CCl4)-induced oxidative stress resulted in disassembly of TJs. Ultrastructural analysis revealed disruption in TJs, Golgi morphology, and expansion of the bile canalicular lumen size in CCl4-treated hepatocytes. The Par complex [Par-3-atypical protein kinase C (aPKC) and Par-6 ternary complex] regulates TJs and lumen formation, and the Par-3-aPKC complex formation was inhibited by CCl4 treatment. Moreover, the antioxidant compound vitamin E prohibited a CCl4-induced disturbance in TJs and Par-3-aPKC complex formation. aPKC phosphorylates Par-3 and down-regulates its own affinity with Par-3. Importantly, aPKC kinase activity and Par-3 phosphorylation were significantly increased in CCl4-treated rat livers. These results indicate that the Par-3-aPKC complex plays a crucial role in the maintenance of hepatocyte polarity and sealing of the bile canalicular lumen. Our findings suggest that bile canalicular lumen expansion might explain the presence of cholestasis in patients with primary biliary cirrhosis and primary sclerosing cholangitis.
authors: Department of Pathology, Tokai University School of Medicine, Isehara, Japan; Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan.
authors: Yosuke
authors: Y
authors: Horikoshi
authors: Division of Host Defense Mechanism, Department of Cell Biology, Tokai University School of Medicine, Isehara, Japan.
authors: Kanae
authors: K
authors: Kitatani
authors: Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
authors: Kentaro
authors: K
authors: Toriumi
authors: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors: Nahoko
authors: N
authors: Fukunishi
authors: Support Center for Medical Research and Education, Tokai University, Isehara, Japan.
authors: Yoshiko
authors: Y
authors: Itoh
authors: Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
authors: Naoya
authors: N
authors: Nakamura
authors: Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Yokohama, Japan.
authors: Shigeo
authors: S
authors: Ohno
authors: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan.
authors: Tatsuya
authors: T
authors: Matsura
authors: Department of Pathology, Tokai University School of Medicine, Isehara, Japan; Division of Host Defense Mechanism, Department of Cell Biology, Tokai University School of Medicine, Isehara, Japan. Electronic address: takekos@is.icc.u-tokai.ac.jp.
authors: Susumu
authors: S
authors: Takekoshi
mesh_terms: D000818:Animals; D001648:Bile Canaliculi / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008954:Models, Biological; D009419:Nerve Tissue Proteins; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism*; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C472451:Pard3 protein, rat; D014810:Vitamin E; D002251:Carbon Tetrachloride; C115015:PKC-3 protein; D011493:Protein Kinase C