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.
Yahagi
Naoya
N
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Shimano
Hitoshi
H
Matsuzaka
Takashi
T
Sekiya
Motohiro
M
Najima
Yuho
Y
Okazaki
Sachiko
S
Okazaki
Hiroaki
H
Tamura
Yoshiaki
Y
Iizuka
Yoko
Y
Inoue
Noriyuki
N
Nakagawa
Yoshimi
Y
Takeuchi
Yoshinori
Y
Ohashi
Ken
K
Harada
Kenji
K
Gotoda
Takanari
T
Nagai
Ryozo
R
Kadowaki
Takashi
T
Ishibashi
Shun
S
Osuga
Jun-ichi
J
Yamada
Nobuhiro
N
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