The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo.
Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential for hepcidin expression. Hepcidin is the key peptide hormone in iron homeostasis, and is secreted predominantly by hepatocytes. HJV expression is detected in hepatocytes, as well as in skeletal and heart muscle. HJV binds BMP6 and increases hepcidin expression presumably by acting as a BMP co-receptor. We characterized the role of hepatocyte HJV in the regulation of BMP6 and hepcidin expression. In HJV-null (Hjv(-/-)) mice that have severe iron overload and marked suppression of hepcidin expression, we detected 4-fold higher hepatic BMP6 mRNA than in wild-type counterparts. These results indicate that Hjv(-/-) mice do not lack BMP6. Furthermore, iron depletion in Hjv(-/-) mice decreased hepatic BMP6 mRNA. Expression of HJV in hepatocytes of Hjv(-/-) mice using an AAV2/8 vector, increased hepatic hepcidin mRNA by 65-fold and phosphorylated Smad1/5/8 in the liver by about 2.5-fold. However, no significant change in BMP6 mRNA was detected in either the liver or the small intestine of these animals. Our results revealed a close correlation of hepatic BMP6 mRNA expression with hepatic iron-loading. Together, our data indicate that the regulation of hepatic BMP6 expression by iron is independent of HJV, and that expression of HJV in hepatocytes plays an essential role in hepcidin expression by potentiating the BMP6-mediated signaling.
Zhang
An-Sheng
AS
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA. zhanga@ohsu.edu
Gao
Junwei
J
Koeberl
Dwight D
DD
Enns
Caroline A
CA
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D055418:Bone Morphogenetic Protein 6 / Q000096:biosynthesis*; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism*; D064451:Hepcidins; D006706:Homeostasis; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D036361:Peptide Hormones / Q000378:metabolism; D015398:Signal Transduction
D023181:Antimicrobial Cationic Peptides; D055418:Bone Morphogenetic Protein 6; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D036361:Peptide Hormones; D007501:Iron