Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation

Natasha T. Snider, Sujith V.W. Weerasinghe, Amika Singla, Jessica M. Leonard, Shinichiro Hanada, Philip C. Andrews, Anna S. Lok, M. Bishr Omary

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Genetic factors impact liver injury susceptibility and disease progression. Prominent histological features of some chronic human liver diseases are hepatocyte ballooning and Mallory-Denk bodies. In mice, these features are induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in a strain-dependent manner, with the C57BL and C3H strains showing high and low susceptibility, respectively. To identify modifiers of DDC-induced liver injury, we compared C57BL and C3H mice using proteomic, biochemical, and cell biological tools. DDC elevated reactive oxygen species (ROS) and oxidative stress enzymes preferentially in C57BL livers and isolated hepatocytes. C57BL livers and hepatocytes also manifested significant down-regulation, aggregation, and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDH knockdown depleted bioenergetic and antioxidant enzymes and elevated hepatocyte ROS, whereas GAPDH overexpression decreased hepatocyte ROS. On the other hand, C3H livers had higher expression and activity of the energy-generating nucleoside-diphosphate kinase (NDPK), and knockdown of hepatocyte NDPK augmented DDC-induced ROS formation. Consistent with these findings, cirrhotic, but not normal, human livers contained GAPDH aggregates and NDPK complexes. We propose that GAPDH and NDPK are genetic modifiers of murine DDC-induced liver injury and potentially human liver disease.

Original languageEnglish (US)
Pages (from-to)217-229
Number of pages13
JournalJournal of Cell Biology
Volume195
Issue number2
DOIs
StatePublished - Oct 17 2011

ASJC Scopus subject areas

  • Cell Biology

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    Snider, N. T., Weerasinghe, S. V. W., Singla, A., Leonard, J. M., Hanada, S., Andrews, P. C., Lok, A. S., & Omary, M. B. (2011). Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation. Journal of Cell Biology, 195(2), 217-229. https://doi.org/10.1083/jcb.201102142