Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Abstract

The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe ؊/؊ mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/ Smad target genes. IntroductionHereditary hemochromatosis associated with HFE mutation (HFE-HH) is a disorder of variable penetrance in which excessive absorption of dietary iron causes iron to accumulate in tissues; in some cases, cellular damage caused by iron leads to organ failure. HFE-HH is characterized by insufficient expression of hepcidin, a circulating peptide hormone produced by the liver in response to several physiologic stimuli, including iron loading. Hepcidin inhibits the absorption of dietary iron and the release of iron from macrophage stores by triggering the internalization and degradation of ferroportin, a cellular iron exporter present on the basolateral membrane of enterocytes and the plasma membrane of macrophages. 1 Both patients with HFE-HH and Hfe knockout (Hfe Ϫ/Ϫ ) mice exhibit hepcidin expression that is inappropriately low relative to their elevated body iron stores, explaining their excessive uptake of dietary iron. [2][3][4] The hepcidin insufficiency in HFE-HH leads to a characteristic distribution of iron stores that is primarily hepatocellular and shows relative sparing of reticuloendothelial cells. [5][6][7] Hepatic expression of a hepcidin transgene was found to inhibit iron accumulation in Hfe Ϫ/Ϫ mice, 3 demonstrating that hepcidin insufficiency is central to the pathogenesis of HFE-HH.The mechanism by which HFE promotes hepcidin expression is not fully understood. HFE, which shares structural homology with major histocompatibility complex class I molecules, heterodimerizes with ␤2-microglobulin. 8 Studies in mouse models suggest that Hfe, which competes with transferrin for binding to transferrin receptor 1 (Tfr1), 9 induces hepcidin expression when dissociated from Tfr1. 10 In vitro studies suggest that interaction of HFE with TFR2, a homolog of TFR1, is also necessary for the induction of hepcidin expression by iron-loaded transferrin. 11 Selective disruption of Hfe in hepatocytes causes hepatic iron overload and hepcidin suppression, indicating that Hfe promotes hepcidin expression in hepatocytes. 12 The bone morphogenetic protein (BMP)/SMAD signaling pathway is a key pathway promoting hepcidin transcription by hepatocytes. Binding of BMPs, members of the transformi...

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

“…The fact that Nrf2 -/-mice fed iron-rich diet develop marked liver injury despite a similar hepatic iron loading to wild-type animals is of great relevance because although the liver is particularly exposed to the toxic effects of iron in excess, rodents are generally resistant to iron-induced liver injury. Mouse models of HH develop the spontaneous iron overload phenotype seen in human patients without developing significant iron-induced liver injury [27,28]. Likewise, the supplementation of mouse diets with carbonyl iron is generally well tolerated, despite the substantial increase in hepatic iron [5,29].…”

Iron refractory iron deficiency anemia

“…Indeed, this has been shown in mouse models. 83 However, from the limited number of studies available, TMPRSS6 SNPs do not seem to modulate iron accumulation in hemochromatosis patients.…”

The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice

“…In theory TFR2 might promote BMP-SMAD signaling for hepcidin production by inhibiting the activity of TMPRSS6, as was hypothesized for HFE, 32 by up-regulating BMP6 or through other unknown mechanisms. For this reason we compared the effect of Tmprss6 inactivation in mice with a total deletion of Tfr2 (Tfr2 We found that in adult Tfr2 -/-mice the heterozygous loss of Tmprss6 slightly reduces the severity of hepatic iron overload and partially reverts the hematologic phenotype, reducing hemoglobin levels.…”