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Experimental Biology and Medicine 232:614-621 (2007)
© 2007 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

TNF-{alpha} Induces Hepatic Steatosis in Mice by Enhancing Gene Expression of Sterol Regulatory Element Binding Protein-1c (SREBP-1c)

Mizuki Endo, Takayuki Masaki, Masataka Seike and Hironobu Yoshimatsu1

Department of Internal Medicine, Faculty of Medicine, Oita University, Hasama, Oita, 879-5593 Japan

To whom requests for reprints should be addressed at 1 Department of Internal Medicine, Faculty of Medicine, Oita University, 1-1 Idaigaoka,Yufu-Hasama, Oita, 879-5593 Japan. E-mail: EMIZUKI{at}med.oita-u.ac.jp

We investigated the effect of tumor necrosis factor-{alpha} (TNF-{alpha}), a member of the proinflammatory cytokine family, on steatosis of the mouse liver by analyzing morphological changes and hepatic triglyceride content in response to TNF-{alpha}. We also examined expression of the sterol regulatory element binding protein-1c gene. Intraperitoneal injection of TNF-{alpha} acutely and dramatically accelerated the accumulation of fat in the liver, as evidenced by histological analysis and hepatic triglyceride content. This treatment increased liver weight, increased serum levels of free fatty acids, and increased fatty acid synthase and sterol regulatory element binding protein-1c mRNA expression. Furthermore, intraperitoneal injection of lipopolysaccaride (LPS) to induce TNF-{alpha} expression also accelerated hepatic fat accumulation. Pretreatment with anti-TNF-{alpha} antibody attenuated the development of LPS-induced fatty change in the liver. Antibody pretreatment not only decreased sterol regulatory element binding protein-1c expression in LPS-treated mice but also attenuated the expression of suppressors of cytokine signaling-3 mRNA. This study suggests that TNF-{alpha}, acting downstream of LPS, increases intrahepatic fat deposition by affecting hepatic lipogenetic metabolism involving sterol regulatory element binding protein-1c.

Key Words: TNF-{alpha} • LPS • liver • SREBP-1c




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