Involvement of SREBPs in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced disruption of lipid metabolism in male guinea pig.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has multiple toxic effects causing a wasting syndrome characterized by a loss of body weight accompanied by a decrease in adipose tissue weight. To elucidate the mechanism behind this syndrome, we investigated the changes in lipid metabolism 7 and 21 days after a single intraperitoneal injection of TCDD at 1 microg/kg body weight to male guinea pigs. TCDD caused the symptoms of the syndrome, body weight loss with a decrease in adipose tissue weight, while it increased the levels of triacylglycerols, total cholesterols, and free fatty acids in plasma. On day 7, TCDD decreased the levels of CCAAT/enhancer binding protein (C/EBP) alpha, peroxisome proliferator activated receptor gamma, and glucose transporter 4, adipogenesis-related factors, in adipose tissue, whereas the levels of retinoid X receptor alpha, C/EBPbeta, C/EBPdelta, and c-Myc remained unchanged. TCDD also reduced the levels of both p125 precursor and p68 active forms of sterol regulatory element binding protein (SREBP)-1 and -2, the lipogenesis-related factors, and downregulated their DNA binding activity in adipose tissue, while it raised the levels of their p68 active forms and increased their DNA binding activity in the liver. TCDD decreased mRNA and protein levels of acetyl-CoA carboxylase and HMG-CoA synthase in the liver and adipose tissue. Similar results were obtained on day 21. These results suggest that TCDD disrupts lipid metabolism through changes in the expression levels of the adipogenesis-related and lipogenesis-related proteins in the liver and adipose tissue, and SREBPs would be involved in the development of the wasting syndrome.
Nishiumi
Shin
S
Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan.
Yabushita
Yoshiyuki
Y
Furuyashiki
Takashi
T
Fukuda
Itsuko
I
Ashida
Hitoshi
H
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D019282:Wasting Syndrome / Q000139:chemically induced*; D015431:Weight Loss / Q000187:drug effects
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004785:Environmental Pollutants; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D047495:PPAR gamma; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; D014280:Triglycerides; D002784:Cholesterol