MTORC1 Inhibition Reduces ER Stress and Ameliorates Alcoholic Liver Injury

Abstract

Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) and endoplasmic reticulum (ER) stress promote hepatic lipid accumulation and insulin resistance. To elucidate the role of mTORC1 in the alcoholic liver disease (ALD), we examined mTORC1 activation and adaptive unfolded protein response (UPR) mechanisms in chronic plus binge ethanol feeding (CB) murine model of alcoholic liver injury. CB resulted in hepatic steatosis, elevation of serum alanine aminotransferase levels, exacerbation of cell apoptosis as indicated as caspase 3 cleavage and poly ADP-ribose polymerase activation. In livers of CB mice, selective UPR genes were upregulated, as evidenced by X-box binding protein splicing, phosphorylation of eIF2α and increased levels of ER chaperone. Furthermore, CB led to defective adaption to prolonged ER stress for ER stress-mediated apoptosis was activated in liver. Similar ER stress responses were achieved/attenuated in mice after challenging with tunicamycin/4-PBA, an ER stress inducer/inhibitor. The steatotic changes were also attributed to lipids accumulation as reflected by sterol regulatory element-binding protein 1 and peroxisome proliferator-activated receptor alpha. Importantly, the activity of mTORC1, as indicated by phosphorylation of S6K1 and 4E-BP1, was increased in CB mice. mTORC1 inhibition by Deptor overexpression or rapamycin injection can restore hepatic ER homeostasis, inhibited lipogenesis, and reduced fatty liver. Specific signaling pathway regulated by mTORC1 was also determined in S6K1 dominant negative CB mice. Therefore, hepatic activation of mTORC1 may play a causal role in ER stress and steatosis related to ALD.