Published online before print December 4, 2008

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080430

Accepted for publication October 14, 2008.

Article

The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Peng Chen^*, Chunying Li, Wenqing Pang^*, Yue Zhao^*, Wei Dong^*, Shiming Wang^*, and Jianfa Zhang^*@

From the Center for Molecular Metabolism,* Nanjing University of Science and Technology, Nanjing; and the Xijing Hospital, Fourth Military Medical University, Xi'an, China

^@ To whom correspondence should be addressed. E-mail: jfzhang{at}mail.njust.edu.cn.

	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 (CCl₄)-induced hepatotoxicity via the modulation of uncoupling protein-2 (Ucp2) gene expression in mice. Hepatic injury after acute CCl₄ injection was monitored in both wild-type and Per2-null mice. At the 12-hour time point after CCl₄ 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 CCl₄ 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 CCl₄ 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- 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.