DNA Methylation Suppresses Liver Hamp Expression in Response to Iron Deficiency After Bariatric Surgery

Abstract

Background: Iron deficiency is extremely common after bariatric surgery. HEPCIDIN, encoded by Hamp, is a hormone that negatively regulates iron homeostasis. We therefore aimed to investigate the alteration of Hamp expression and its related regulatory factors to explore the probable role of DNA methylation in regulating Hamp expression in the context of iron deficiency after bariatric surgery. Methods: RNA-seq was performed using rat liver tissue after either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery to identify differentially expressed genes (DEGs) between the bariatric surgery and sham group. Hamp expression were measured by quantitative PCR and ELISA, respectively. The DNA methylation level was determined using MassARRAY EpiTYPER. Iron status, erythrocyte parameters and inflammation factors were also assessed. Results: RNA-seq data showed that Hamp expression in liver changed most dramatically in RYGB-operated rats. Both the mRNA expression of Hamp and the abundance of its protein product HEPCIDIN-25 were markedly decreased after bariatric surgery compared with sham, while SG-operated rats showed marginally higher Hamp expression than RYGB-operated rats. The DNA methylation level of the Hamp promoter region was significant higher in RYGB-operated rats than sham, while SG rats increased slightly in DNA methylation. Consistent with the change of HEPCIDIN-25, serum iron was significantly lower for both bariatric groups than sham and particularly low in RYGB. Conclusions: Our data demonstrate that elevated DNA methylation of the Hamp promoter region suppresses its expression, and this epigenetic modification likely occurs in reaction to iron deficiency after bariatric surgery, helping to maintain system iron homeostasis. Funding Statement: The current study was supported by grants from National Key R&D Program of China (2016YFC1304801), the Outstanding Academic Leaders of Shanghai Health System program (2017BR008), the Yangtze River Scholar program, the National Natural Science Foundation of China (81800708), and the Shanghai Sixth People’s Hospital (YNLC201725). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All animals were maintained and used in accordance with the guidelines of the Animal Care and Use Committee of Shanghai Sixth People’s Hospital.