Abstract
Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that histones are avidly modified by 4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (ob/ob) and high-fat feeding models of obesity. Proteomic evaluation of in vitro 4-HNE- modified histones led to the identification of both Michael and Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy hexenal (4-HHE) and 10 sites of 4-HNE histone modification in visceral adipose tissue. In summary, these results characterize adipose histone carbonylation as a redox-linked epigenomic mark associated with metabolic disease and aging.
Highlights
Obesity is a chronic, low-grade inflammatory state in which increased pro-inflammatory signaling leads to oxidative stress, altered cellular metabolism, and the development of insulin resistance [1]
Paralleling evidence reveals the crosstalk between inflammation and adipose mitochondrial biology, and recent work from Schaum et al [8] on gene expression and Yu et al [9] on targeted pathway proteomics have both indicated that adipose tissue may serve as a sentinel of age-dependent processes
We find that the core histones are specific targets of carbonylation and that these modifications accumulate in adipose tissue as a consequence of high-fat feeding (HFD) and of aging
Summary
Low-grade inflammatory state in which increased pro-inflammatory signaling leads to oxidative stress, altered cellular metabolism, and the development of insulin resistance [1]. Paralleling evidence reveals the crosstalk between inflammation and adipose mitochondrial biology, and recent work from Schaum et al [8] on gene expression and Yu et al [9] on targeted pathway proteomics have both indicated that adipose tissue may serve as a sentinel of age-dependent processes Both reports indicate that mitochondria from white adipose are reprogrammed as a function of age and adiposity, highlighting the importance of oxidative stress response pathways in metabolic disease. Recent work from Hauck et al has shown that the nucleus is a major site for protein carbonylation in adipose tissue [15] This was an unanticipated result that suggests a new mechanistic connection between oxidative stress and nuclear regulatory events. 4-HNE and 4-HHE, despite their chemical similarity, modify different sites, introducing the concept that each oxidation event may initiate distinct signaling outcomes
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