title: Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model.
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 wild-type 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.
authors.affiliation: Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Otani
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Okubo
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Takako
authors.initials: T
authors.lastname: Kikuch
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.forename: Haruya
authors.initials: H
authors.lastname: Ohno
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D065626:Non-alcoholic Fatty Liver Disease; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse