Autophagy in Alcohol-Induced Multiorgan Injury: Mechanisms and Potential Therapeutic Targets

Figure 1

The major molecular pathways and targets in alcohol-induced autophagy changes in hepatocytes. Ethanol modulates autophagy through multiple mechanisms. (1) Ethanol-induced autophagy requires ethanol metabolism and ROS production. ROS may activate autophagy by further suppressing mTOR. (2) Alcohol (ethanol) consumption inhibits methionine synthase (MS) resulting in decreased methionine and S-adenosylmethionine (SAM) levels. Methionine and SAM inhibit autophagy by activating mTORC1. Thus it is possible that ethanol-induced decreased methionine and SAM will inhibit mTORC1 resulting in autophagy activation although this has not been directly tested in the alcohol model (?). (3) Ethanol may also suppress Akt through the upregulation of PTEN and in turn inhibits mTORC1 to induce autophagy. (4) Ethanol-induced impaired AMPK and Akt may counteract each other on mTOR, and impaired Akt plays a dominant role toward the inhibition of mTOR. (5) Decreased Akt can also trigger autophagy through the activation of FoxO3 by promoting the dephosphorylation and nuclear retention of FoxO3. Increased NADH/NAD⁺ ratio through ethanol metabolism inhibits Sirt1 activity resulting in increased acetylated FoxO3. Increased acetylated FoxO3 may decrease FoxO3-mediated expression of autophagy genes, which can be abolished by resveratrol that activates Sirt1. (6) Other AMPK-independent pathways remain to be determined in alcohol-induced autophagy (?). (7) mTORC1 negatively regulates autophagy through direct phosphorylation of ULK1 to inactivate ULK1 complex activity. ULK1 directly phosphorylates Beclin-1 and enhances VPS34 kinase activity to promote autophagy. AMPK positively regulates autophagy by suppressing mTORC1 activity through phosphorylation of TSC2 and raptor and by promoting VPS34 kinase activity through phosphorylation of Beclin-1. Activated VPS34 increases the production of phosphatidylinositol 3-phosphate (PI3P), which promotes the biogenesis of autophagosomes although the activities of ULK1 and VPS34 after alcohol exposure still remain to be determined (?).