17-Oxo-docosahexaenoic acid induces Nrf2-mediated expression of heme oxygenase-1 in mouse skin in vivo and in cultured murine epidermal cells

Muhammad Usman Jamil; Jimin Kim; Hye-Won Yum; Seong Hoon Kim; Su-Jung Kim; Do-Hee Kim; Nam-Chul Cho; Hye-Kyung Na; Young-Joon Surh

doi:10.1016/j.abb.2019.108156

17-Oxo-docosahexaenoic acid induces Nrf2-mediated expression of heme oxygenase-1 in mouse skin in vivo and in cultured murine epidermal cells

Arch Biochem Biophys. 2020 Jan 15:679:108156. doi: 10.1016/j.abb.2019.108156. Epub 2019 Oct 17.

Authors

Muhammad Usman Jamil¹, Jimin Kim¹, Hye-Won Yum², Seong Hoon Kim², Su-Jung Kim³, Do-Hee Kim⁴, Nam-Chul Cho⁵, Hye-Kyung Na⁶, Young-Joon Surh⁷

Affiliations

¹ Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
² Tumor Microenvironment Global Core Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
³ Tumor Microenvironment Global Core Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
⁴ Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
⁵ C&C Research Laboratories, DRC, Sungyunkwan University, Suwon, 16419, South Korea.
⁶ Department of Food Science and Biotechnology, College of Knowledge-based Services Engineering, Sungshin Women's University, Seoul, 01133, South Korea.
⁷ Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea. Electronic address: surh@snu.ac.kr.

PMID: 31629711
DOI: 10.1016/j.abb.2019.108156

Abstract

Recently, growing attention has been given to new classes of bioactive lipid mediators derived from ω-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), especially in the context of their role as endogenous signal modulators. One such molecule is 17-oxo-DHA, generated from DHA by the action of COX2 and a dehydrogenase. The redox-sensitive transcription factor, Nrf2 plays a key role in cellular stress responses. In the present study, the effects of 17-oxo-DHA on Nrf2-mediated expression of cytoprotective enzymes were examined in mouse skin in vivo and cultured murine epidermal JB6 cells. Topical application of 17-oxo-DHA markedly elevated the nuclear localization of Nrf2 and expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 in hairless mouse skin. In contrast to 17-oxo-DHA, the non-electrophilic metabolic precursor 17-hydroxy-DHA was a much weaker inducer of Nrf2 activation and its target protein expression. Likewise, 17-oxo-DHA significantly enhanced nuclear translocation and transcriptional activity of Nrf2 with concomitant upregulation of HO-1 expression in cultured JB6 cells. 17-Oxo-DHA was a much stronger inducer of Nrf2-mediated antioxidant response than its parent molecule, DHA. HO-1 expression was abolished in Nrf2 knockdown JB6 cells or embryo fibroblasts from Nrf2 knock out mice. 17-Oxo-DHA also markedly reduced the level of Keap1 protein by inducing ubiquitination. Mutation of Cys151 and Cys273 in Keap1 abrogated 17-oxo-DHA-induced ubiquitination and proteasome-mediated degradation of Keap1 as well as HO-1 expression, suggesting that these cysteine residues are putative sites for 17-oxo-DHA binding. Further, Keap1 degradation stimulated by 17-oxo-DHA coincided with accumulation of the autophagy substrate, p62/SQSTM1.

Keywords: 17-Oxo-DHA; Docosahexaenoic acid; Heme oxygenase-1; Mouse skin; Nrf2; Omega-3 polyunsaturated fatty acids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Docosahexaenoic Acids / metabolism
Docosahexaenoic Acids / pharmacology*
Epidermis / drug effects
Epidermis / metabolism*
Female
Gene Expression Regulation, Enzymologic / drug effects*
HEK293 Cells
Heme Oxygenase-1 / metabolism*
Humans
Kelch-Like ECH-Associated Protein 1 / chemistry
Kelch-Like ECH-Associated Protein 1 / metabolism
Mice
Molecular Docking Simulation
NF-E2-Related Factor 2 / metabolism*
Protein Conformation

Substances

Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Docosahexaenoic Acids
Heme Oxygenase-1