DNA methylation suppresses liver Hamp expression in response to iron deficiency after bariatric surgery

Background: Iron deficiency is extremely common after bariatric surgery. HEPCIDIN, encoded by Hamp, is a hormone that negatively regulates iron homeostasis.

Objectives: We aimed to investigate the alteration of Hamp expression and related regulatory factors to explore the probable role of DNA methylation in modulating Hamp expression in the context of iron deficiency after bariatric surgery.

Setting: Laboratories of Diabetes Institute.

Methods: RNA-seq was performed using rat liver tissue after either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy surgery to identify differentially expressed genes between the bariatric surgery and sham group. Hamp expression were measured by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The DNA methylation level was determined using MassARRAY EpiTYPER. Iron status, erythrocyte parameters, and inflammation factors were assessed.

Results: RNA-seq data showed that liver Hamp expression changed most dramatically in RYGB-operated rats. Both the mRNA expression of Hamp and the abundance of its protein product HEPCIDIN-25 decreased markedly after bariatric surgery compared with sham, while sleeve gastrectomy-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 sleeve gastrectomy 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, this epigenetic modification likely occurs in reaction to iron deficiency after bariatric surgery, helping to maintain system iron homeostasis.