HIF-2α, but not HIF-1α, promotes iron absorption in mice

Abstract

HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical roles in regulating intestinal iron absorption. To explore this idea, we first established that the mouse duodenum, the site of iron absorption in the intestine, is hypoxic and generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium. Using these mice, we found that HIF-1α was not necessary for iron absorption, whereas HIF-2α played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter. Specific deletion of Hif2a led to a decrease in serum and liver iron levels and a marked decrease in liver hepcidin expression, indicating the involvement of an induced systemic response to counteract the iron deficiency. This finding may provide a basis for the development of new strategies, specifically in targeting HIF-2α, to improve iron homeostasis in patients with iron disorders.

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

“…Moreover, actomyosin contraction is central to homeostatic and pathologic IEC shedding and barrier restitution (27). Epithelial function and barrier integrity is further regulated by low oxygen tension, through HIF-elicited adaptive pathways (28,29). Notable for the present work, a recent study highlighted a role for epithelial Hif-2α in mediating proinflammatory epithelial responses in murine models of chemical and bacterial colitis, in contrast to the barrier protective program elicited by Hif-1α (30).…”

Culture of human intestinal epithelial cell using the dissociating enzyme thermolysin and endothelin-3

“…Available online April 30, 2010. Published May 14, 2010. Epithelial cells lining the intestinal mucosa play a key role in the homeostasis of the organisms (1,2). Depending on their location in the intestinal tract, they not only play a central role in absorptive and secretory functions, but also have the ability to protect the organism from various pathogens and toxins found even under the normal conditions in the intestine, providing an effective barrier to the complex antigenic load of intestinal contents (3).…”

Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction

“…For instance, cell type-specific regulatory mechanisms other than oxygen tension modulate the expression and transcriptional activity of HIF-1α and HIF-2α with differing and even opposing effects [11][12][13][14][15] . Knockout studies in mice additionally yield distinct phenotypes [16][17][18][19] . Consistently, HIF-1α and HIF-2α exert differential and antagonistic effects in chondrocytes.…”