Amino acid deprivation induces TXNIP expression by NRF2 downregulation

Abstract TXNIP is an essential regulator of cellular metabolism, including glucose homeostasis, fatty acid synthesis, cholesterol accumulation, and is implicated in metabolic diseases such as obesity, type 2 diabetes, and atherosclerosis. However, how TXNIP expression is regulated in response to amino acid (AA) deprivation is not well understood. In the present study, deprivation of AAs, especially arginine, glutamine, lysine, and methionine, induced TXNIP expression in H460 non-small cell lung cancer cells. Unexpectedly, TXNIP induction by AA deprivation was dependent on NRF2 downregulation, but not ATF4 activation. Furthermore, N-acetyl-L-cysteine, a scavenger of reactive oxygen species (ROS), prevented TXNIP expression in H460 cells deprived of AA. Taken together, TXNIP expression by AA deprivation is mediated by ROS production by NRF2 downregulation. Our findings suggest that TXNIP expression might be associated with the redox homeostasis of AA metabolism.