Abstract
Ethanol exposure promotes the development of steatohepatitis, which can progress to end stage liver disease. Kupffer cells have been documented to play a key role in the genesis and progression of alcoholic liver disease with ethanol exposure enhancing Kupffer cell activation. In the present study, we identified the binding of hexokinase II to the mitochondria as a requirement for LPS-induced activation of Kupffer cells and its potentiation by ethanol. LPS and ethanol exposure induced a reduction in sirtuin-3 activity. In turn, the decline of sirtuin-3 activity led to the activation of cyclophilin-D, which mediated an increased binding of hexokinase II to the mitochondria. Suppression of cyclophilin-D expression or enforced detachment of hexokinase II from the mitochondria abrogated the LPS- and ethanol-induced stimulation of Kupffer cells, preventing NADPH oxidase and inflammasome activation. Moreover, activation of AMP-activated protein kinase restored sirtuin-3 activity, thereby preventing LPS and ethanol from stimulating the binding of hexokinase II to the mitochondria and precluding NADPH oxidase and inflammasome activation.
Highlights
Detachment of Hexokinase II from Mitochondria Abrogates Ethanol- and LPS-induced Inflammasome Activation—Kupffer cells isolated from control- or ethanol-fed rats were transfected with either a non-targeting siRNA or siRNA targeting cyclophilin-D
Following a 16-h incubation, the cells were transfected with 50 nM non-targeting siRNA or siRNA targeting cyclophilin-D
The present study demonstrated that in Kupffer cells LPSinduced inflammasome activation is dependent on a rapid increase of aerobic glycolysis that is potentiated by exposure to ethanol
Summary
Results: Ethanol exposure potentiates activation of Kupffer cells by promoting the translocation of hexokinase to mitochondria. Tified the binding of hexokinase II to the mitochondria as a The inflammasomes have three basic constituents, one of requirement for LPS-induced activation of Kupffer cells and its which is a sensor component that is heterogeneous among the potentiation by ethanol. Aerobic glycolysis is critically dependent on the ability of hexokinase I or II to bind to mitochondria through the voltagedependent anion channel, an outer mitochondrial membrane protein [8, 11, 12]. Upon activation of Kupffer cells, there was a rapid translocation of hexokinase II to the mitochondria that was mediated by an LPS- and ethanol-induced decrease of sirtuin-3 activity, resulting in a stimulation of cyclophilin-D. Activation of AMPK reversed LPS- and ethanol-induced inhibition of sirtuin-3, thereby preventing LPS- and ethanol-induced Kupffer cell activation
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