Identification of 5′ AMP-activated Kinase as a Target of Reactive Aldehydes during Chronic Ingestion of High Concentrations of Ethanol

Abstract

Background: Carbonylation of proteins contributes to increased hepatocellular damage during alcoholic liver disease. Results: In a murine model of alcoholic liver disease, AMPK is covalently modified by reactive aldehydes reducing activity. Conclusion: Inhibition of AMPK activity by reactive aldehydes contributes to increased steatosis in alcoholic liver disease. Significance: This is the first report of AMPK carbonylation and inhibition during conditions of increased oxidative stress.

Role of phosphodiesterase-4 in alcohol-induced organ injury.

“…Consequently, decrease in 4HNE-adduct formation could have contributed to increased activity of AMPKα and a resultant inactivation of ACC. These results are in agreement with the studies demonstrating that 4HNE-mediated carbonylation of AMPKα impairs its kinase function [128]. Taken together, these findings indicate that PDE4 inhibition mediated increase of antioxidant enzymes, AMPKα function and decreased activity of ACC also contributed to decreased lipid accumulation in alcohol fed mice.…”

“…AMPK mediated phosphorylation of inactivates Acetyl-CoA-carboxylase (ACC), a rate limiting enzyme in fatty acid synthesis, leads to inactivation of ACC and results in decreased lipid accumulation in the liver [62]. There are conflicting reports on alcohol effect on AMPK phosphorylation on Threonine 172 which activates AMPK kinase [62,112,[124][125][126][127][128]. More recently, it has been shown that increased 4NHE levels lead to carbonylation of AMPK which inhibits its kinase activity [128].…”

“…There are conflicting reports on alcohol effect on AMPK phosphorylation on Threonine 172 which activates AMPK kinase [62,112,[124][125][126][127][128]. More recently, it has been shown that increased 4NHE levels lead to carbonylation of AMPK which inhibits its kinase activity [128]. Based on our observation that PDE4 inhibition attenuated oxidative stress and 4HNE adduct formation in alcohol fed mice, we examined whether PDE4 inhibition affected AMPK activity [59,129].…”

“…More recently, increased carbonylation of AMPK due to increased HNE production in alcohol fed mice has been shown to inhibit AMPK kinase function [128]. This loss of function led to decreased phosphorylation and activation of ACC [128].…”

“…This loss of function led to decreased phosphorylation and activation of ACC [128]. Increased oxidative stress and reactive aldehydes is well documented with alcohol consumption [145][146][147][148].…”