Deletion of the stress‐response protein REDD1 promotes ceramide‐induced retinal cell death and JNK activation

ABSTRACT The role of dyslipidemia in the development of retinal dysfunction remains poorly understood. Using an animal model of diet‐induced obesity/pre‐type 2 diabetes, we investigated molecular defects in the retina arising from consumption of a diet high in saturated fats and sugars ( i.e ., a Western diet). We found that feeding mice a Western diet increased the abundance of retinal sphingolipids, attenuated protein kinase B (Akt) phosphorylation, enhanced JNK activation, and increased retinal cell death. When we used palmitate or C6‐ceramide (Cer) to assess sphingolipid‐mediated signaling in cultured murine and human cells, we observed similar effects on Akt, JNK, and cell death. Furthermore, both Western diet and C6‐Cer exposure enhanced expression of the stress‐response protein regulated in development and DNA damage response 1 (REDD1) and loss of REDD1 increased C6‐Cer‐induced JNK activation and cell death. Exogenous REDD1 expression repressed JNK‐mediated phosphorylation in cultured cells. We found that thioredoxin‐interacting protein (TXNIP) expression was elevated in REDD1–deficient cell lines and C6‐Cer promoted TXNIP expression in both wild‐type and REDD1–deficient cells. Likewise, TXNIP knockdown attenuated JNK activation and caspase 3 cleavage after either C6‐Cer exposure or REDD1 deletion. The results support a model wherein Cer‐induced REDD1 expression attenuates TXNIP‐dependent JNK activation and retinal cell death.—Dai, W., Miller, W. P., Toro, A. L., Black, A. J., Dierschke, S. K., Feehan, R. P., Kimball, S. R., Dennis, M. D. Deletion of the stress‐response protein REDD1 promotes ceramide‐induced retinal cell death and JNK activation. FASEB J. 32, 6883–6897 (2018). www.fasebj.org