title: Tumour necrosis factor-α promotes liver ischaemia-reperfusion injury through the PGC-1α/Mfn2 pathway.
abstract: Tumour necrosis factor (TNF)-α has been considered to induce ischaemia-reperfusion injury (IRI) of liver which is characterized by energy dysmetabolism. Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α and mitofusion2 (Mfn2) are reported to be involved in the regulation of mitochondrial function. However, whether PGC-1α and Mfn2 form a pathway that mediates liver IRI, and if so, what the underlying involvement is in that pathway remain unclear. In this study, L02 cells administered recombinant human TNF-α had increased TNF-α levels and resulted in down-regulation of PGC-1α and Mfn2 in a rat liver IRI model. This was associated with hepatic mitochondrial swelling, decreased adenosine triphosphate (ATP) production, and increased levels of reactive oxygen species (ROS) and alanine aminotransferase (ALT) activity as well as cell apoptosis. Inhibition of TNF-α by neutralizing antibody reversed PGC-1α and Mfn2 expression, and decreased hepatic injury and cell apoptosis both in cell culture and in animals. Treatment by rosiglitazone sustained PGC-1α and Mfn2 expression both in IR livers, and L02 cells treated with TNF-α as indicated by increased hepatic mitochondrial integrity and ATP production, reduced ROS and ALT activity as well as decreased cell apoptosis. Overexpression of Mfn2 by lentiviral-Mfn2 transfection decreased hepatic injury in IR livers and L02 cells treated with TNF-α. However, there was no up-regulation of PGC-1α. These findings suggest that PGC-1α and Mfn2 constitute a regulatory pathway, and play a critical role in TNF-α-induced hepatic IRI. Inhibition of the TNF-α or PGC-1α/Mfn2 pathways may represent novel therapeutic interventions for hepatic IRI.
authors.affiliation: Department of Urology Surgery, Cancer Institute, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Wenbo
authors.initials: W
authors.lastname: Ke
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Luo
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Qichang
authors.initials: Q
authors.lastname: Zheng
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D020558:GTP Phosphohydrolases; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000378:metabolism*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
keywords: ischaemia-reperfusion injury; liver; mitofusion2; peroxisome proliferator-activated receptor-γ co-activator-1α; tumour necrosis factor alpha