A functional interplay between the two BMP-SMAD pathway inhibitors TMPRSS6 and FKBP12 regulates < em > hepcidin < /em > expression < em > in vivo < /em >

Am J Physiol Gastrointest Liver Physiol. 2024 Jan 22. doi: 10.1152/ajpgi.00305.2023. Online ahead of print.ABSTRACTThe Activin A Receptor type I ALK2 is a critical component of the BMP-SMAD signaling that, in the presence of ligands, phosphorylates cytosolic SMAD1/5/8 and modulates important biological processes, including bone formation and iron metabolism. In hepatocytes, the BMP-SMAD pathway controls the expression of hepcidin, the liver peptide hormone that regulates body iron homeostasis via the BMP receptors ALK2 and ALK3, and the hemochromatosis proteins. The main negative regulator of the pathway in the liver is the transmembrane serine protease 6 (TMPRSS6), which downregulates hepcidin by cleaving the BMP coreceptor hemojuvelin. ALK2 function is inhibited also by the immunophilin FKBP12 which maintains the receptor in an inactive conformation.FKBP12 sequestration by tacrolimus or its silencing upregulates hepcidin in primary hepatocytes and in vivo, in acute but not chronic settings. Interestingly, gain-of-function mutations in ALK2 that impair FKBP12 binding to the receptor and activate the pathway cause a bone phenotype in patients affected by Fibrodysplasia Ossificans Progressiva, but not hepcidin and iron metabolism dysfunction. This observation suggests that additional mechanisms are active in the liver to compensate for the increased BMP-SMAD signaling. Here we demonstrate that Fkbp12 downregulation in hepatocytes by antisense oligonucleotide treatment upregula...
Source: Am J Physiol Gastroi... - Category: Gastroenterology Authors: Source Type: research