The Protective Role of Per2 Against Carbon Tetrachloride-Induced Hepatotoxicity

Peng Chen^*, Chunying Li, Wenqaing 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

Period 2 (Per2) is a key component of the core clock oscillatorand is involved in regulating a number of different biologicalprocesses and pathways. Here we report that Per2 plays a protectiverole in carbon tetrachloride (CCl₄)-induced hepatotoxicity viathe modulation of uncoupling protein-2 (Ucp2) gene expressionin mice. Hepatic injury after acute CCl₄ injection was monitoredin both wild-type and Per2-null mice. At the 12-hour time pointafter CCl₄ treatment, many more vacuolations were observed inthe liver tissues of Per2-null mice whereas fatty tissue degenerationprimarily occurred in the liver tissues of wide-type mice. Serumalanine and aspartate aminotransferase activities were elevatedin Per2-null mice compared with wide-type mice at 24 hours afterCCl₄ treatment, which was in agreement with the observationof significantly larger areas of centrilobular necrosis in thelivers of Per2-null mice. A deficit of the Per2 gene enhancedUcp2 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. Theabsence of Per2 expression caused a dramatic elevation of Clockexpression and influenced Ucp2 through a mechanism that involveda Clock-controlled PPAR- ${alpha}$ signal transduction pathway. Our studiessuggest that the Per2 gene functions in hepatocyte protectionfrom chemical toxicants via the regulation of hepatic Ucp2 geneexpression levels.