p53 involvement in the pathogenesis of fatty liver disease.
Obesity is a major health problem in industrialized societies, and fatty liver disease (hepatic steatosis) is common in obese individuals. Oxidative stress originating from increased intracellular levels of fatty acids has been implicated as a cause of hepatocellular injury in steatosis, although the precise mechanisms remain to be elucidated. p53, widely known as a tumor suppressor, has been shown often to be activated in stressed cells, inducing cell cycle arrest or death. Here we demonstrate that p53 is involved in the molecular mechanisms of hepatocellular injury associated with steatosis. We found that p53 in the nucleus is induced in the liver from two mouse models of fatty liver disease, ob/ob and a transgenic mouse model that overexpresses an active form of sterol regulatory element-binding protein-1 in the liver (TgSREBP-1), the one with obesity and the other without obesity. This activation of the p53 pathway leads to the elevation of p21 mRNA expression, which can be considered an indicator of p53 activity, because ob/ob mice lacking p53 generated by targeting gene disruption exhibited the complete restoration of the p21 elevation to wild type levels. Consistent with these results, the amelioration of hepatic steatosis caused by Srebp-1 gene disruption in ob/ob mice lowered the p21 expression in a triglyceride content-dependent manner. Moreover, p53 deficiency in ob/ob mice resulted in a marked improvement of plasma alanine aminotransferase levels, demonstrating that p53 is involved in the mechanisms of hepatocellular injury. In conclusion, we revealed that p53 plays an important role in the pathogenesis of fatty liver disease.
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Naoya
N
Yahagi
Hitoshi
H
Shimano
Takashi
T
Matsuzaka
Motohiro
M
Sekiya
Yuho
Y
Najima
Sachiko
S
Okazaki
Hiroaki
H
Okazaki
Yoshiaki
Y
Tamura
Yoko
Y
Iizuka
Noriyuki
N
Inoue
Yoshimi
Y
Nakagawa
Yoshinori
Y
Takeuchi
Ken
K
Ohashi
Kenji
K
Harada
Takanari
T
Gotoda
Ryozo
R
Nagai
Takashi
T
Kadowaki
Shun
S
Ishibashi
Jun-ichi
J
Osuga
Nobuhiro
N
Yamada
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53