title: The protective role of Per2 against carbon tetrachloride-induced hepatotoxicity.
abstract: Period 2 (Per2) is a key component of the core clock oscillator and is involved in regulating a number of different biological processes and pathways. Here we report that Per2 plays a protective role in carbon tetrachloride (CCl(4))-induced hepatotoxicity via the modulation of uncoupling protein-2 (Ucp2) gene expression in mice. Hepatic injury after acute CCl(4) injection was monitored in both wild-type and Per2-null mice. At the 12-hour time point after CCl(4) treatment, many more vacuolations were observed in the liver tissues of Per2-null mice whereas fatty tissue degeneration primarily occurred in the liver tissues of wide-type mice. Serum alanine and aspartate aminotransferase activities were elevated in Per2-null mice compared with wide-type mice at 24 hours after CCl(4) treatment, which was in agreement with the observation of significantly larger areas of centrilobular necrosis in the livers of Per2-null mice. A deficit of the Per2 gene enhanced Ucp2 gene expression levels in the liver. As a consequence, intracellular levels of ATP markedly decreased in the liver, allowing increased production of toxic CCl(4) derivatives. The absence of Per2 expression caused a dramatic elevation of Clock expression and influenced Ucp2 through a mechanism that involved a Clock-controlled PPAR-alpha signal transduction pathway. Our studies suggest that the Per2 gene functions in hepatocyte protection from chemical toxicants via the regulation of hepatic Ucp2 gene expression levels.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.forename: Wenqaing
authors.initials: W
authors.lastname: Pang
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.forename: Shiming
authors.initials: S
authors.lastname: Wang
authors.forename: Jianfa
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D056926:CLOCK Proteins; D002251:Carbon Tetrachloride / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D056950:Period Circadian Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000071246:Uncoupling Protein 2
chemical_list: D018797:Cell Cycle Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D047493:PPAR alpha; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D002251:Carbon Tetrachloride; D056926:CLOCK Proteins; C538944:Clock protein, mouse