The non‐coding RNA gadd7 is a regulator of lipotoxic‐induced ROS and ER stress

Abstract

To elucidate molecular events in the lipotoxicity pathway, we used retroviral promoter trap mutagenesis to generate a mutant Chinese hamster ovary (CHO) cell line resistant to palmitate‐induced cell death. In this mutant, insertion of the provirus has disrupted one allele of the non‐coding RNA (ncRNA) growth arrest DNA‐damage inducible gene 7 (gadd7), creating a model of haploinsufficiency. Knockdown of gadd7 in wild type (wt) cells also causes palmitate‐resistance. Because reactive oxygen species (ROS) induces gadd7 and palmitate generates ROS, we hypothesized that palmitate induces gadd7 expression in a ROS‐dependent manner. Palmitate treatment of wt cells induces gadd7 expression, but this is diminished by co‐treatment with an antioxidant. Although gadd7 haploinsufficient cells generate ROS in response to palmitate, induction is decreased compared to wt cells. These data suggest a feed forward loop between gadd7 and ROS generation. Since ROS generation contributes to palmitate‐induced ER stress, we assessed gadd7's role in palmitate‐induced ER stress. Induction of ER stress related genes is significantly reduced in palmitate treated gadd7 haploinsufficient and knockdown cells, indicating that gadd7 expression is necessary for palmitate‐induced ER stress. Together these data implicate a ncRNA in propagation of oxidative stress and in regulation of ER stress responses.NIH F31 (RT) and DK064989 (JES)