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

Weiwei Dai, William P. Miller, Allyson L. Toro, Adam J. Black, Sadie K. Dierschke, Robert P. Feehan, Scot Kimball, Michael Dennis

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6883-6897
Number of pages15
JournalFASEB Journal
Volume32
Issue number12
DOIs
StatePublished - Dec 1 2018

Fingerprint

Ceramides
Cell death
Nutrition
Heat-Shock Proteins
Thioredoxins
Cell Death
Chemical activation
Sphingolipids
Phosphorylation
Cells
Proteins
Diet
Proto-Oncogene Proteins c-akt
Palmitates
Medical problems
Dyslipidemias
Sugars
Caspase 3
Type 2 Diabetes Mellitus
DNA Damage

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Dai, Weiwei ; Miller, William P. ; Toro, Allyson L. ; Black, Adam J. ; Dierschke, Sadie K. ; Feehan, Robert P. ; Kimball, Scot ; Dennis, Michael. / Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation. In: FASEB Journal. 2018 ; Vol. 32, No. 12. pp. 6883-6897.
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Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation. / Dai, Weiwei; Miller, William P.; Toro, Allyson L.; Black, Adam J.; Dierschke, Sadie K.; Feehan, Robert P.; Kimball, Scot; Dennis, Michael.

In: FASEB Journal, Vol. 32, No. 12, 01.12.2018, p. 6883-6897.

Research output: Contribution to journalArticle

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