Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis
Ting Guo,
Shaohua Hu,
Weijue Xu,
Jin Zhou,
Feng Chen,
Tingting Gao,
Wenqian Qu,
Faling Chen,
Zhibao Lv,
Li Lu
Affiliations
Ting Guo
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Shaohua Hu
Department of Clinical Laboratory, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Weijue Xu
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Jin Zhou
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Feng Chen
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Tingting Gao
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Wenqian Qu
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Faling Chen
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China
Zhibao Lv
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China; Corresponding author
Li Lu
Department of General Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China; Corresponding author
Summary: Epigenetic alterations are especially important in necrotizing enterocolitis (NEC). Here, we reported that histone deacetylase 8 (HDAC8) plays a previously unknown role in modulating arginine metabolism via acetylation of histone 3 lysine 9 (acetyl-H3K9) regulation during the pathogenesis of NEC. We found that HDAC8 was upregulated in humans and mice intestinal samples with NEC, while selective inhibition of HDAC8 expression ameliorated NEC. HDAC8 regulates enzymes involved in the metabolic conversion of proline to arginine (PRODH, PRODH2, OAT, and OTC) and arginine to ornithine (ARG1). The results showed that H3K9ac signal in the PRODH/PRODH2 promoter region was mediated by HDAC8. Additionally, the decreased concentration of butyric acid was strongly correlated with elevated HDAC8 levels and circulating arginine, which may result from an unbalanced Firmicutes/Bacteroidetes ratio. These results reveal previously underappreciated roles of microbial metabolites and HDAC8 to coordinate the arginine metabolism during NEC development.
