Summary Iron deficiency and iron overload are among the most prevalent nutritional disorders worldwide. Duodenal cytochrome b (DcytB) and divalent metal transporter 1 (DMT1) are regulators of iron absorption. Their expression is increased during high systemic requirements for iron, but the molecular mechanisms that regulate DcytB and DMT1 expression are undefined. Hypoxia inducible factor (HIF) signaling was induced in the intestine following acute iron deficiency in the duodenum, resulting in activation of DcytB and DMT1 expression and an increase in iron uptake. DcytB and DMT1 were demonstrated as direct HIF-2α target genes. Genetic disruption of HIF signaling in the intestine abolished the adaptive induction of iron absorption following iron deficiency, resulting in low systemic iron and hematological defects. These results demonstrate that HIF signaling in the intestine is a critical regulator of systemic iron homeostasis.

Background: HNF4␣ is a key factor regulating hepatocyte differentiation and liver-specific functions. Results: Acute disruption of HNF4␣ in the adult liver causes rapid hepatocyte proliferation through direct and indirect control of multiple pathways. Conclusion: HNF4␣ is necessary to maintain the differentiated state of hepatocytes in adult liver. Significance: HNF4␣ expression maintains normal liver function, and its loss stimulates hepatocytes proliferation, possibly leading to cancer.