Metabolic depletion of ATP by fructose inversely controls CD95-and tumor necrosis factor receptor 1-mediated hepatic apoptosis

Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined ill different models of murine liver injury whether and how metab olically induced alterations of hepatocyte ATP levels control receptor-medi ated apoptosis. ATP was depleted either in primary hepatocytes or in vivo b y various phosphate-trapping carbohydrates such as fructose. After the acti vation of the tumor necrosis factor (TNF) receptor or CD95, the extent of h epatocyte apoptosis and liver damage was quantified. TNF-induced cell death was completely blocked in ATP-depleted hepatocyte cultures, whereas apopto sis mediated by CD95 was enhanced. Similarly, acute TNF-induced liver injur y in mice was entirely inhibited by ATP depletion with ketohexoses, whereas CD95-mediated hepatotoxicity was enhanced. ATP depletion prevented mitocho ndrial cytochrome c release, loss of mitochondrial membrane potential, acti vation of type II caspases, DNA fragmentation, and cell lysis after exposur e to TNF. The extent of apoptosis inhibition correlated with the severity o f ATP depletion, and TNF-induced apoptosis was restored when ATP was replet ed by increasing the extracellular phosphate concentration. Our study demon strates that TNF-induced hepatic apoptosis can be selectively and reversibl y blocked upstream of mitochondrial dysfunction by ketohexose-mediated ATP depletion.