Obesity-induced protein carbonylation in murine adipose tissue regulates the DNA-binding domain of nuclear zinc finger proteins

Amy K. Hauck, Tong Zhou, Wendy Hahn, Raphael Petegrosso, Rui Kuang, Yue Chen, David A. Bernlohr

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

In obesity-linked insulin resistance, oxidative stress in adipocytes leads to lipid peroxidation and subsequent carbonylation of proteins by diffusible lipid electrophiles. Reduction in oxidativestressattenuatesproteincarbonylationandinsulinresis-tance, suggesting that lipid modification of proteins may play a role in metabolic disease, but the mechanisms remain incompletely understood. Herein, we show that in vivo, diet-induced obesity in mice surprisingly results in preferential carbonylation of nuclear proteins by 4-hydroxy-trans-2,3-nonenal (4-HNE) or 4-hydroxy-trans-2,3-hexenal (4-HHE). Proteomic and structural analyses revealed that residues in or around the sites of zinc coordination of zinc finger proteins, such as those containing the C2H2 or MATRIN, RING, C3H1, or N4-type DNA-binding domains, are particularly susceptible to carbonylation by lipid aldehydes. These observations strongly suggest that carbonylation functionally disrupts protein secondary structure supported by metal coordination. Analysis of one such target, the nuclear protein estrogen-related receptor (ERR-), showed that ERR- is modified by 4-HHE in the obese state. In vitro carbonylation decreased the DNA-binding capacity of ERR- and correlated with the obesity-linked down-regulation of many key genes promoting mitochondrial bioenergetics. Taken together, these findings reveal a novel mechanistic connection between oxidative stress and metabolic dysfunction arising from carbonylation of nuclear zinc finger proteins, such as the transcriptional regulator ERR-.

Original languageEnglish (US)
Pages (from-to)13464-13476
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number35
DOIs
StatePublished - Aug 31 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant R01 DK084669 and the Minnesota Agricultural Experiment Station (to D. A. B.), National Institutes of Health Grant T32 GM008347 (to A. K. H.), and the CAPES Foundation, Ministry of Education of Brazil (BEX 13250/13-2) (to R. P.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
This work was supported by National Institutes of Health Grant R01 DK084669 and the Minnesota Agricultural Experiment Station (to D. A. B.), National Institutes of Health Grant T32 GM008347 (to A. K. H.), and the CAPES Foun-dation, Ministry of Education of Brazil (BEX 13250/13-2) (to R. P.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2018 Hauck et al.

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