Ceramide Induces Human Hepcidin Gene Transcription through JAK/STAT3 Pathway

PloS One
Sizhao LuDuygu Dee Harrison-Findik

Abstract

Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of lipid and iron metabolism is largely unknown. We investigated the role of lipid intermediate, ceramide in the regulation of human hepcidin gene, HAMP. Human hepatoma HepG2 cells were treated with cell-permeable ceramide analogs. Ceramide induced significant up-regulation of HAMP mRNA expression in HepG2 cells. The effect of ceramide on HAMP expression was mediated through transcriptional mechanisms because it was completely blocked with actinomycin D treatment. Reporter assays also confirmed the activation of 0.6 kb HAMP promoter by ceramide. HepG2 cells treated with ceramide displayed increased phosphorylation of STAT3, JNK, and NF-κB proteins. However, ceramide induced the binding of STAT3, but not NF-κB or c-Jun, to HAMP promoter, as shown by the chromatin immunoprecipitation assays. The mutation of STAT3 response element within 0.6 kb HAMP promoter region significantly inhibited the stimulatory effect of ceramide on HAMP promoter activity. Similarly, the inhibition of STAT3...Continue Reading

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Citations

Oct 11, 2017·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Hirofumi HamanoToshiaki Tamaki
Oct 27, 2018·Pharmaceuticals·Stephanie RockfieldMeera Nanjundan
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Aug 1, 2020·BioMed Research International·Ke PeiYunlun Li
Jan 28, 2021·Cell Death Discovery·Philma Glora MuthurajSathish Kumar Natarajan
Jul 3, 2021·Biomedicines·Philma Glora MuthurajSathish Kumar Natarajan

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Methods Mentioned

BETA
transfection
transfections
PCR
electrophoresis
immunoprecipitation
ChIP

Software Mentioned

BLAST
MatInspector
SPSS
Primer

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