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

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 oxidative stress attenuates protein carbonylation and insulin resistance, 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 γ (ERR-γ), showed that ERR-γ is modified by 4-HHE in the obese state. In vitro carbonylation decreased the DNA-binding capacity of ERR-γ 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-γ.

• Authors: Amy K Hauck, Tong Zhou, Wendy Hahn, Raphael Petegrosso, Rui Kuang, Yue Chen, David A Bernlohr
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 35 Pg. 13464-13476 (08 31 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 30012885 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Hauck et al.

Chemical References

• Aldehydes
• DNA-Binding Proteins
• Nuclear Proteins
• 4-hydroxy-2-hexenal
• 4-hydroxy-2-nonenal

Topics

• Adipose Tissue (metabolism)
• Aldehydes (metabolism)
• Amino Acid Sequence
• Animals
• Cell Nucleus (metabolism)
• DNA-Binding Proteins (chemistry, metabolism)
• Mice
• Nuclear Proteins (chemistry, metabolism)
• Obesity (metabolism)
• Oxidative Stress
• Protein Carbonylation
• Zinc Fingers