TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c).
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.
Endo
Mizuki
M
Department of Internal Medicine, Faculty of Medicine, Oita University, Idaigaoka,Yufu-Hasama, Oita, Japan.
Masaki
Takayuki
T
Seike
Masataka
M
Yoshimatsu
Hironobu
H
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity*; D019014:fas Receptor / Q000235:genetics
D000906:Antibodies; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008070:Lipopolysaccharides; D047493:PPAR alpha; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D064429:Fatty Acid Synthases