title: Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.
abstract: Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.
authors.affiliation: a Faculty of Pharmacy, Zhejiang Pharmaceutical College, Ningbo 315100, PR China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yao
authors.affiliation: b Beijing Centre For Physical & Chemical Analysis, Beijing 100050, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: a Faculty of Pharmacy, Zhejiang Pharmaceutical College, Ningbo 315100, PR China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Li
authors.affiliation: b Beijing Centre For Physical & Chemical Analysis, Beijing 100050, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Cheng
authors.affiliation: a Faculty of Pharmacy, Zhejiang Pharmaceutical College, Ningbo 315100, PR China.
authors.forename: Ai-Bin
authors.initials: AB
authors.lastname: Lin
authors.affiliation: a Faculty of Pharmacy, Zhejiang Pharmaceutical College, Ningbo 315100, PR China.
authors.forename: Jun-Ge
authors.initials: JG
authors.lastname: Qu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013752:Tetracycline / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001713:Biphenyl Compounds; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D014280:Triglycerides; D051742:Transcription Factor CHOP; C477843:bicyclol; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D013752:Tetracycline
keywords: ER stress; apoptose; apoptosis; bicyclol; fatty liver; stress du RE; stéatose hépatique; tetracycline; tétracycline