title: Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation.
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.
authors: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. nsnider@umich.edu
authors: Natasha T
authors: NT
authors: Snider
authors: Sujith V W
authors: SV
authors: Weerasinghe
authors: Amika
authors: A
authors: Singla
authors: Jessica M
authors: JM
authors: Leonard
authors: Shinichiro
authors: S
authors: Hanada
authors: Philip C
authors: PC
authors: Andrews
authors: Anna S
authors: AS
authors: Lok
authors: M Bishr
authors: MB
authors: Omary
mesh_terms: D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics*; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D008107:Liver Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D011725:Pyridines; D017382:Reactive Oxygen Species
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D011725:Pyridines; D017382:Reactive Oxygen Species; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D009701:Nucleoside-Diphosphate Kinase