Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model

Yusuke Nakatsu, Yuichiro Otani, Hideyuki Sakoda, Jun Zhang, Ying Guo, Hirofumi Okubo, Akifumi Kushiyama, Midori Fujishiro, Takako Kikuch, Toshiaki Fukushima, Haruya Ohno, Yoshihiro Tsuchiya, Hideaki Kamata, Akiko Nagamachi, Toshiya Inaba, Fusanori Nishimura, Hideki Katagiri, Shin Ichiro Takahashi, Hiroki Kurihara, Takafumi Uchida & 1 others Tomoichiro Asano

Research output: Contribution to journalArticle

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Abstract

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by simultaneous fat accumulation and chronic inflammation in the liver. In this study, Pin1 expression was revealed to be markedly increased in the livers of mice with methionine choline-deficient (MCD) diet-induced NASH, a rodent model of NASH. In addition, Pin1 KO mice were highly resistant to MCD induced NASH, based on a series of data showing simultaneous fat accumulation, chronic inflammation, and fibrosis in the liver. In terms of Pin1-induced fat accumulation, it was revealed that the expression levels of peroxisome proliferator-activated receptor α and its target genes were higher in the livers of Pin1 KO mice than in controls. Thus, resistance of Pin1 KO mice to hepatic steatosis is partially attributable to the lack of Pin1-induced down-regulation of peroxisome proliferator-activated receptor α, although multiple other mechanisms are apparently involved. Another mechanism involves the enhancing effect of hematopoietic Pin1 on the expressions of inflammatory cytokines such as tumor necrosis factor and monocyte chemoattractant protein 1 through NF-κB activation, eventually leading to hepatic fibrosis. Finally, to distinguish the roles of hematopoietic or nonhematopoietic Pin1 in NASH development, mice lacking Pin1 in either nonhematopoietic or hematopoietic cells were produced by bone marrow transplantation between wildtype and Pin1 KO mice. The mice having nonhematopoietic Pin1 exhibited fat accumulation without liver fibrosis on the MCD diet. Thus, hepatic Pin1 appears to be directly involved in the fat accumulation in hepatocytes, whereas Pin1 in hematopoietic cells contributes to inflammation and fibrosis. In summary, this is the first study to demonstrate that Pin1 plays critical roles in NASH development. This report also raises the possibility that hepatic Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy for NASH.

Original languageEnglish
Pages (from-to)44526-44535
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number53
DOIs
Publication statusPublished - Dec 28 2012

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Liver
Rodentia
Fats
Choline
Methionine
Peroxisome Proliferator-Activated Receptors
Nutrition
Proteins
Inflammation
Liver Cirrhosis
Chemokine CCL2
Fibrosis
Diet
Bone
Tumor Necrosis Factor-alpha
Genes
Chemical activation
Non-alcoholic Fatty Liver Disease
Bone Marrow Transplantation
Cytokines

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Nakatsu, Y., Otani, Y., Sakoda, H., Zhang, J., Guo, Y., Okubo, H., ... Asano, T. (2012). Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model. Journal of Biological Chemistry, 287(53), 44526-44535. https://doi.org/10.1074/jbc.M112.397133

Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model. / Nakatsu, Yusuke; Otani, Yuichiro; Sakoda, Hideyuki; Zhang, Jun; Guo, Ying; Okubo, Hirofumi; Kushiyama, Akifumi; Fujishiro, Midori; Kikuch, Takako; Fukushima, Toshiaki; Ohno, Haruya; Tsuchiya, Yoshihiro; Kamata, Hideaki; Nagamachi, Akiko; Inaba, Toshiya; Nishimura, Fusanori; Katagiri, Hideki; Takahashi, Shin Ichiro; Kurihara, Hiroki; Uchida, Takafumi; Asano, Tomoichiro.

In: Journal of Biological Chemistry, Vol. 287, No. 53, 28.12.2012, p. 44526-44535.

Research output: Contribution to journalArticle

Nakatsu, Y, Otani, Y, Sakoda, H, Zhang, J, Guo, Y, Okubo, H, Kushiyama, A, Fujishiro, M, Kikuch, T, Fukushima, T, Ohno, H, Tsuchiya, Y, Kamata, H, Nagamachi, A, Inaba, T, Nishimura, F, Katagiri, H, Takahashi, SI, Kurihara, H, Uchida, T & Asano, T 2012, 'Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model', Journal of Biological Chemistry, vol. 287, no. 53, pp. 44526-44535. https://doi.org/10.1074/jbc.M112.397133
Nakatsu, Yusuke ; Otani, Yuichiro ; Sakoda, Hideyuki ; Zhang, Jun ; Guo, Ying ; Okubo, Hirofumi ; Kushiyama, Akifumi ; Fujishiro, Midori ; Kikuch, Takako ; Fukushima, Toshiaki ; Ohno, Haruya ; Tsuchiya, Yoshihiro ; Kamata, Hideaki ; Nagamachi, Akiko ; Inaba, Toshiya ; Nishimura, Fusanori ; Katagiri, Hideki ; Takahashi, Shin Ichiro ; Kurihara, Hiroki ; Uchida, Takafumi ; Asano, Tomoichiro. / Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 53. pp. 44526-44535.
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abstract = "Nonalcoholic steatohepatitis (NASH) is a disorder characterized by simultaneous fat accumulation and chronic inflammation in the liver. In this study, Pin1 expression was revealed to be markedly increased in the livers of mice with methionine choline-deficient (MCD) diet-induced NASH, a rodent model of NASH. In addition, Pin1 KO mice were highly resistant to MCD induced NASH, based on a series of data showing simultaneous fat accumulation, chronic inflammation, and fibrosis in the liver. In terms of Pin1-induced fat accumulation, it was revealed that the expression levels of peroxisome proliferator-activated receptor α and its target genes were higher in the livers of Pin1 KO mice than in controls. Thus, resistance of Pin1 KO mice to hepatic steatosis is partially attributable to the lack of Pin1-induced down-regulation of peroxisome proliferator-activated receptor α, although multiple other mechanisms are apparently involved. Another mechanism involves the enhancing effect of hematopoietic Pin1 on the expressions of inflammatory cytokines such as tumor necrosis factor and monocyte chemoattractant protein 1 through NF-κB activation, eventually leading to hepatic fibrosis. Finally, to distinguish the roles of hematopoietic or nonhematopoietic Pin1 in NASH development, mice lacking Pin1 in either nonhematopoietic or hematopoietic cells were produced by bone marrow transplantation between wildtype and Pin1 KO mice. The mice having nonhematopoietic Pin1 exhibited fat accumulation without liver fibrosis on the MCD diet. Thus, hepatic Pin1 appears to be directly involved in the fat accumulation in hepatocytes, whereas Pin1 in hematopoietic cells contributes to inflammation and fibrosis. In summary, this is the first study to demonstrate that Pin1 plays critical roles in NASH development. This report also raises the possibility that hepatic Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy for NASH.",
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AU - Guo, Ying

AU - Okubo, Hirofumi

AU - Kushiyama, Akifumi

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