Hexokinase II binding to Mitochondria is Necessary for Kupffer cell Activation and is Potentiated by Ethanol Exposure [Bioenergetics]
August 5th, 2014 by Shulga, N., Pastorino, J. G.
Ethanol exposure promotes the development of steatohepatitis that 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 report, we identify the binding of hexokinase II to the mitochondria as being required for LPS induced activation of Kupffer cells and its potentiation by ethanol. LPS and ethanol exposure induce a reduction in sirtuin-3 activity. In turn, the decline of sirtuin-3 activity leads to the activation of cyclophilin-D, which mediates 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 AMPK 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.