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Comprehensive analysis of alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated transcriptomics and metabolomics

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Abstract

Understanding mechanisms of liver injury can enable better preclinical testing and clinical management of patients. Carbon tetrachloride (CCl4), used extensively as a model hepatotoxicant, induces lipid perturbation and increases in plasma bile acids (BAs). An integrated transcriptomics and metabolomics approach was employed to investigate CCl4-induced alterations in lipid and BA metabolism. Sprague–Dawley rats were treated orally with corn oil, 50 (low dose, LD) or 2,000 mg CCl4/kg/d (high dose, HD). Animals were sacrificed at 6, 24 or 72 h. Terminal blood was collected for clinical chemistry and metabolomics analyses. Livers were harvested for histopathology, metabolomics and transcriptomics analyses. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the treated groups with the greatest increases observed in the HD group at 24 and 72 h. Blood cholesterol and triglycerides (TGs) were significantly decreased in the HD group at both 24 and 72 h, and hepatocyte vacuolization was observed at these timepoints. Consistent with the clinical chemistry and histopathological data, metabolomics results showed that levels of total fatty acids increased in the liver but decreased in the blood in the HD group at the 24 and 72 h timepoints. This suggested that lipids accumulate in the liver. Primary BAs increased in both liver and blood, while secondary and conjugated BAs decreased in the liver and increased in the blood, which indicated that the BA conjugation pathway and that BA uptake by the liver were inhibited by CCl4. Results from this study provide a better understanding of the mechanisms of CCl4-induced hepatotoxicity.

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Acknowledgments

The authors thank Alan Warbritton for expert technical assistance with the photomicrographs.

Conflict of interests

All authors (J. Sun, T. Schmitt, L. K. Schnackenberg, L. Pence, Y. Ando, J. Greenhaw, X. Yang, S. Slavov, K. J. Davis, W. F. Salminen, D. L. Mendrick, and R. D. Beger) declare that they have no conflict of interest.

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The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration.

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Author notes

  1. William F. Salminen

    Present address: PAREXEL International, Sarasota, FL, USA

  2. Yosuke Ando

    Present address: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan

Authors and Affiliations

  1. Division of Systems Biology, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR, 72079, USA

    Jinchun Sun, Thomas Schmitt, Laura K. Schnackenberg, Lisa Pence, Yosuke Ando, James Greenhaw, Xi Yang, Svetoslav Slavov, William F. Salminen, Donna L. Mendrick & Richard D. Beger

  2. Toxicologic Pathology Associates, Inc. (TPA), National Center for Toxicological Research, US FDA, Jefferson, AR, USA

    Kelly Davis

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  1. Jinchun Sun
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Correspondence to Jinchun Sun.

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Sun, J., Schmitt, T., Schnackenberg, L.K. et al. Comprehensive analysis of alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated transcriptomics and metabolomics. Metabolomics 10, 1293–1304 (2014). https://doi.org/10.1007/s11306-014-0665-7

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  • DOI: https://doi.org/10.1007/s11306-014-0665-7

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