Metabolic Depletion of Atp by Fructose Inversely Controls Cd95- and Tumor Necrosis Factor Receptor 1–Mediated Hepatic Apoptosis

Abstract

Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined in different models of murine liver injury whether and how metabolically induced alterations of hepatocyte ATP levels control receptor-mediated apoptosis. ATP was depleted either in primary hepatocytes or in vivo by various phosphate-trapping carbohydrates such as fructose. After the activation of the tumor necrosis factor (TNF) receptor or CD95, the extent of hepatocyte apoptosis and liver damage was quantified. TNF-induced cell death was completely blocked in ATP-depleted hepatocyte cultures, whereas apoptosis mediated by CD95 was enhanced. Similarly, acute TNF-induced liver injury in mice was entirely inhibited by ATP depletion with ketohexoses, whereas CD95-mediated hepatotoxicity was enhanced. ATP depletion prevented mitochondrial cytochrome c release, loss of mitochondrial membrane potential, activation of type II caspases, DNA fragmentation, and cell lysis after exposure to TNF. The extent of apoptosis inhibition correlated with the severity of ATP depletion, and TNF-induced apoptosis was restored when ATP was repleted by increasing the extracellular phosphate concentration. Our study demonstrates that TNF-induced hepatic apoptosis can be selectively and reversibly blocked upstream of mitochondrial dysfunction by ketohexose-mediated ATP depletion.

Lysosomes and Fas-mediated liver cell death

“…The percentage of unsedimentable β-galactosidase is low before aFas injection ( 10 %) and is not modified by such an injection. Even when apoptosis caused by aFas injection is stimulated by a fructose injection [22], one does not observe an increase in unsedimentable β-galactosidase activity. The total and unsedimentable activities of three other lysosomal hydrolases (β-glucuronidase, cathepsin C and cathepsin B) were measured in the control homogenates and in the homogenates obtained 80 min after aFas injection.…”

Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling

“…Murine hepatocytes were isolated by the two-step collagenase perfusion method and cultured as described 36 . In brief, 8-10-week-old mice were killed by tail vein injection of pentobarbital (2.5 mg per 10 g body weight dissolved in isotonic saline containing 1,000 I.E.…”

Apoptosis to necrosis switching downstream of apoptosome formation requires inhibition of both glycolysis and oxidative phosphorylation in a BCL-XL- and PKB/AKT-independent fashion

“…8 Caspase pathways can be silenced by an array of factors, such as inhibitory peptide or proteins, 9 nitrative/oxidative stress, 10 or energy depletion, 11 and, in turn, the cell can switch from an apoptotic to a necrotic-like death process. 7 Prevention of ATP production was shown to inhibit caspase activation in some experimental models, [12][13][14] and the molecules that couple apoptosis regulation and energy metabolism are currently under investigation. The Bcl-2 family protein Bcl-X L was reported to prevent cell death by maintaining oxidative phosphorylation even in conditions of metabolite deprivation.…”