Snider et al. report that differential expression of two key metabolic enzymes may explain why some people are more susceptible to liver damage.
Some forms of liver disease, particularly steatohepatitis, are marked by the formation of misfolded protein aggregates called Mallory-Denk bodies (MDBs). Not all patients display these aggregates, however, and some research suggests that MDBs are more common in patients of Hispanic origin. Different strains of mice also show different susceptibilities to MDB formation when their livers are damaged by the drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which induces oxidative stress. Snider et al. analyzed the proteomes of livers from two different mouse strains to investigate the cause of their different sensitivities to DDC.
Many metabolic and oxidative stress–related enzymes were differentially expressed in the livers of C57BL (MDB-susceptible) and C3H (MBD-resistant) mice, resulting in higher levels of reactive oxygen species (ROS) in C57BL hepatocytes after DDC treatment. Prominent among these enzymes were two general “housekeeping” proteins: the glycolytic and redox-sensing enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and the energy-generating protein nucleoside-diphosphate kinase (NDPK), both of which showed reduced expression in C57BL livers and were downregulated further by DDC.
Depleting GAPDH or NDPK by RNAi elevated ROS levels similarly to DDC treatment, whereas overexpressing GAPDH prevented DDC from inducing ROS production in C57BL hepatocytes. Snider et al. think that low GAPDH and NDPK expression causes C57BL livers to be metabolically and oxidatively stressed even under basal conditions and therefore more sensitive to additional stresses like DDC. The researchers also found that GAPDH is aggregated in cirrhotic patient livers, suggesting that similar mechanisms may contribute to liver disease severity in humans.