title: Acetoacetate induces hepatocytes apoptosis by the ROS-mediated MAPKs pathway in ketotic cows.
abstract: Dairy cows with ketosis are characterized by oxidative stress, hepatic damage, and hyperketonemia. Acetoacetate (AA) is the main component of ketone bodies in ketotic cows, and is associated with the above pathological process. However, the potential mechanism was not illuminated. Therefore, the aim of this study was to investigate the mechanism of AA-induced hepatic oxidative damage in ketotic cows. Compared with healthy cows, ketotic cows exhibited severe oxidative stress and hepatic damage. Moreover, the extent of hepatic damage and oxidative stress had a positive relationship with the AA levels. In vitro, AA treatment increased reactive oxygen species (ROS) content and further induced oxidative stress and apoptosis of bovine hepatocytes. In this process, AA treatment increased the phosphorylation levels of JNK and p38MAPK and decreased the phosphorylation level of ERK, which could increase p53 and inhibit nuclear factor E2-related factor 2 (Nrf2) expression, nuclear localization, and DNA-binding affinity, thereby inducing the overexpression of pro-apoptotic molecules Bax, Caspase 3, Caspase 9, PARP and inhibition of anti-apoptotic molecule Bcl-2. Antioxidant N-acetylcysteine (NAC) treatment or interference of MAPKs pathway could attenuate the hepatocytes apoptosis induced by AA. Collectively, these results indicate that AA triggers hepatocytes apoptosis via the ROS-mediated MAPKs pathway in ketotic cows.
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Xiliang
authors.initials: X
authors.lastname: Du
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Chenxu
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Guowen
authors.initials: G
authors.lastname: Liu
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062,, Jilin, China.
authors.forename: Xinwei
authors.identifier: http://orcid.org/0000-0002-0765-677X
authors.initials: X
authors.lastname: Li
mesh_terms: D000090:Acetoacetates / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007662:Ketosis; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000090:Acetoacetates; D017382:Reactive Oxygen Species; C016635:acetoacetic acid
keywords: acetoacetate; apoptosis; ketotic cows; mitogen-activated protein kinases; reactive oxygen species