Enho Mutations Causing Low Adropin: A Possible Pathomechanism of MPO-ANCA Associated Lung Injury

Abstract

BackgroundMyeloperoxidase (MPO) anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis commonly causes life-threatening pulmonary alveolar hemorrhage or fibrosis. Only a limited number of candidate gene variants have been explored, but hitherto, are not widely confirmed. In the present study, we investigated the importance of energy homeostasis associated gene (Enho) mutations and adropin deficiency in the development of MPO-ANCA associated lung injury.MethodsWe analyzed the peripheral blood mononuclear cells from 152 unrelated patients and 220 population-matched healthy individuals for genetic variations in Enho. Functional studies with adropin knockout (AdrKO) on C57BL/6J mice were also performed.FindingsSequencing revealed six patients with p.Ser43Thr and that five patients shared Cys56Trp amino acid substitution in Enho. Serum concentration of adropin was significantly lower in patients than that of the healthy subjects (P < 0.0001), especially those with Enho mutations. In vivo, homo- and heterozygous carriers of the null adropin allele exhibited MPO-ANCA associated pulmonary alveolar hemorrhage as compared to wild-type mice. AdrKO mice exhibit reduced eNOS (Ser1177) and Akt1 (Ser473) phosphorylation and loss of Treg cells.InterpretationOur findings indicate that the presence of Enho mutations or adropin-deficiency is a probable molecular basis for the initial events triggered in MPO-ANCA associated lung injury.

Adropin deficiency worsens HFD-induced metabolic defects

“…Moreover, c.216 C>T heterozygous synonymous mutation (ENST00000399775.2: p.Tyr72Tyr) ( Figure 1e ) was also found in the family (II3, 5 and III3, 4, 6, 7, 9, 11 and IV1, 2, 3), and originated from the mother (II6); the mutation was located at the predicted tyrosine phosphorylation site. 13 Both mutations were not detected in the other five healthy members (II9 and III2, 5, 8, 15) without the diagnostic feature of diabetes or FP. The other nine patients harbored c.*238T>C mutation at the 3′ UTR of Enho ( Figure1e ).…”

“…Other examples are N -acetyltransferase, 24 , 25 glucose-6-phosphate dehydrogenase (G6PD), transcription factor AP-2, and heat shock protein, which contribute to susceptibility to type 2 diabetes and FP disease by inhibiting glucose-induced insulin secretion in pancreatic β cells or naringin attenuated insulin resistance 26 ; adropin deficiency downregulated peNOS whose uncoupling contributes to endothelial dysfunction. 13 , 27 To further explore the signal transduction pathways involved in adropin-attenuated impaired angiogenesis in diabetic mice, we examined the effects of adropin on eNOS phosphorylation in AdrKO mice, which showed reduced eNOS (Ser1177) phosphorylation within perivascular cells from the kidney and pancreas, as well as neuronal cells.…”

“…Assignment of metabolites was identified based on the published literature and databases such as HMDB, KEGG, PubChem compound database and SMPDB. 13 Subsequent pathway mapping analysis was conducted with the IPA metabolomics model ( http://www.Ingenuity.com/products/ pathways_analysis.html ).…”

“…It was shown that adropin is mainly regulated by miRNAs, along with the only gene responsible for nonshivering thermogenesis (mitochondrial uncoupling protein 1, or UCP1) in brown adipose tissue. 13 Moreover, adropin-deficiency exhibits loss of T reg and results in autoimmune diseases. 13 …”

A Review of Adropin as the Medium of Dialogue between Energy Regulation and Immune Regulation

“…In addition to metabolic disorders and cardiovascular diseases, adropin has been shown as a potential antiinflammatory factor in other inflammatory diseases. Gao et al [37] demonstrated that ENHO-/-mice showed MPO-ANCA-related pulmonary vasculitis, which is an autoimmune disease. It is well known that Treg cell is a subset of T cells that control autoimmune reactivity, and their deficiency can lead to autoimmune diseases.…”