Protective effect of bicyclol on tetracycline-induced fatty liver in mice.
Peroxisome proliferators-activated receptor alpha (PPARalpha) and oxidative stress are two important pathological factors in non-alcoholic fatty liver disease (NAFLD). Tetracycline-induced fatty liver was partly due to the disturbance of mitochondrial fatty acids beta-oxidation regulated by PPARalpha. Bicyclol was found to protect against high fat diet-induced fatty liver through modulating PPARalpha and clearing reactive oxygen species (ROS). The present study was performed to further investigate the effect of bicyclol on tetracycline-induced fatty liver and related mechanism in mice. Bicyclol (75, 150, 300 mg/kg) was given orally three times in two consecutive days. Tetracycline (200 mg/kg) was injected intraperitoneally 1h after the last administration of bicyclol. Oxidative stress, mitochondrial function, PPARalpha and its target genes were evaluated by biochemical and RT-PCR analysis. The activity of CYP4A was assessed by liquid chromatography/mass spectrometry (LC/MS) method. Bicyclol significantly protected against tetracycline-induced fatty liver by reducing the accumulation of hepatic lipids and elevation of serum aminotransferase. In addition, bicyclol remarkably alleviated the over-production of thiobarbituric acid-reactive substance. The reduced activity of mitochondrial respiratory chain (MRC) complexes I and IV and mitochondrial permeability transition (MPT) were also improved by bicyclol. Furthermore, bicyclol inhibited the decrease of PPARalpha expression and its target genes, including long-chain acyl CoA dehydrogenase (LCAD), acetyl CoA oxidase (AOX) and CYP4A at mRNA and enzyme activity level. Bicyclol protected against tetracycline-induced fatty liver mainly through modulating the disturbance of PPARalpha pathway and ameliorating mitochondrial function.
Yu
Hong-Yan
HY
Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, [corrected] Chinese Academy of Medical Sciences, No. 1, Xian Nong Tan Street, Beijing 100050, PR China.
Wang
Bao-Lian
BL
Zhao
Jing
J
Yao
Xiao-Min
XM
Gu
Yu
Y
Li
Yan
Y
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013752:Tetracycline; D013997:Time Factors
D001713:Biphenyl Compounds; D005227:Fatty Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D047493:PPAR alpha; D020011:Protective Agents; C477843:bicyclol; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A; D042962:Acyl-CoA Oxidase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D003576:Electron Transport Complex IV; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D042967:Electron Transport Complex I; D013752:Tetracycline