The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Abstract

Transcription factor Nrf2 (NF-E2-related factor 2) regulates a broad cytoprotective response to environmental stresses. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. Whereas the Keap1-Nrf2 system plays important roles in oxidative stress response and metabolism, the roles Nrf2 plays in the prevention of diabetes mellitus remain elusive. Here we show that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic knockdown (Keap1^flox/−) markedly suppresses the onset of diabetes. When Keap1^flox/− mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1^flox/− also prevented high-calorie-diet-induced diabetes. Oral administration of the Nrf2 inducer CDDO-Im {oleanolic acid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole} also attenuated diabetes in db/db mice. Nrf2 induction altered antioxidant-, energy consumption-, and gluconeogenesis-related gene expression in metabolic tissues. Thus, the Keap1-Nrf2 system is a critical target for preventing the onset of diabetes mellitus.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00225-13.

ACKNOWLEDGMENTS

This work was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas and for Scientific Research from the Ministry of Education, Science, Sports and Culture (MEXT) and the Takeda Foundation, Naito Foundation, Japanese Foundation for Applied Enzymology, and Tohoku University Global COE Program for Conquest of Signal Transduction Diseases with Network Medicine from JSPS.

We thank Sayoi Inomata for mouse genotyping, Fumiko Date for immunohistochemistry, and the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support.

Y.F., H.M., and T.N. are employees of Mochida Pharmaceutical Co. Ltd.