Suppression of hepatic fat accumulation by highly purified eicosapentaenoic acid prevents the progression of d-galactosamine-induced hepatitis in mice fed with a high-fat/high-sucrose diet.
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we assessed the importance of hepatic fat accumulation on the progression of hepatitis. BALB/cA mice were fed with a standard diet (STD) or a high-fat and high-sucrose diet (HFHSD) for 14 days followed by intraperitoneal injection of d-galactosamine (DGalN) or vehicle. After 20-21 h, plasma and liver tissue were collected and analyzed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma were increased significantly in HFHSD-fed mice treated with DGalN compared to STD-fed mice treated with DGalN. This exacerbation by the HFHSD was also observed in the plasma soluble tumor necrosis factor receptor (sTNFR) levels, and hepatic levels of reactive oxygen species (ROS) and the fibrogenic gene expression, such as tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), connective tissue growth factor (CTGF) and osteopontin (OPN) in HFHSD-fed mice treated with DGalN. The triglyceride contents of the liver were significantly increased by the HFHSD. When eicosapentaenoic acid (EPA), a suppressor of sterol regulatory element binding protein 1 (SREBP-1), was administered to HFHSD-fed mice, the sensitivity of DGalN, as a result of plasma ALT and AST levels, was suppressed accompanied by reduced plasma sTNFR2 level and hepatic levels of triglyceride, ROS, and fibrogenic parameters, and by increased plasma adiponectin levels. These data suggest that the progression of steatotic liver injury closely depends on the accumulation of fat in the liver and is prevented by EPA through the suppression of the fatty liver change.
Kajikawa
Satoshi
S
Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
Harada
Tsuyoshi
T
Kawashima
Akiko
A
Imada
Kazunori
K
Mizuguchi
Kiyoshi
K
D052242:Adiponectin / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D055513:Connective Tissue Growth Factor / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D019422:Dietary Sucrose / Q000008:administration & dosage*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005688:Galactosamine / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006505:Hepatitis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D052242:Adiponectin; D004041:Dietary Fats; D019422:Dietary Sucrose; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D051780:Sterol Regulatory Element Binding Protein 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D014280:Triglycerides; D055513:Connective Tissue Growth Factor; D005688:Galactosamine; D015118:Eicosapentaenoic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase