Role of Intestinal HIF-2α in Health and Disease

Abstract

The intestine is supported by a complex vascular system that undergoes dynamic and transient daily shifts in blood perfusion, depending on the metabolic state. Moreover, the intestinal villi have a steep oxygen gradient from the hypoxic epithelium adjacent to the anoxic lumen to the relative higher tissue oxygenation at the base of villi. Due to the daily changes in tissue oxygen levels in the intestine, the hypoxic transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. HIF-2α is essential in maintaining proper micronutrient balance, the inflammatory response, and the regenerative and proliferative capacity of the intestine following an acute injury. However, chronic activation of HIF-2α leads to enhanced proinflammatory response, intestinal injury, and colorectal cancer. In this review, we detail the major mechanisms by which HIF-2α contributes to health and disease of the intestine and the therapeutic implications of targeting HIF-2α in intestinal diseases.

Keywords: Crohn's disease; colon cancer; hypoxia; inflammatory bowel disease; iron; ulcerative colitis.

Figure 1

Regulation of hypoxia-inducible factor (HIF) function. (a) HIF-1α and HIF-1α have highly homologous modular domains: a basic helix-loop-helix (bHLH) domain, a Per-Arnt-Sim (PAS) domain, and a transactivation domain that includes the N-terminal activation domain (N-TAD) and the C-terminal activation domain (C-TAD). The homology of each domain is represented as a percentage. The two proline residues in the oxygen-dependent degradation domain (ODD) are critical for the stability of HIF-1α and HIF-2α. (b) Prolyl hydroxylase domain (PHD) enzymes use molecular oxygen, 2-oxoglutarate (2-OG), and ferric iron (Fe³⁺) to hydroxylate the two proline residues on HIF. This step is required for the binding of the Von Hippel–Lindau (VHL) tumor suppressor protein. VHL binding recruits E3 ubiquitin (Ub) ligases, which degrade HIFα subunits under normoxic conditions through proteasome-mediated degradation. A decrease in cellular oxygen inhibits PHD activity, leading to HIFα stabilization, binding to ARNT, and increased HIFα transcriptional activity. Other abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; CBP, CREB-binding protein.

Figure 2

Mechanisms that mediate HIF-2α specificity. HIF-2α specificity is regulated at the levels of mRNA expression, mRNA translation, protein stability, and transcriptional activity. Blue arrows indicate an increase in expression or activity, and red arrows denote a decrease in expression or activity. Abbreviations: Ac, acetylation; ARNT, aryl hydrocarbon receptor nuclear translocator; CBP, CREB-binding protein; EIF, eukaryotic initiation factor; HAF, hypoxia-associated factor; IL, interleukin; IRP1, iron-regulatory protein 1; KLHL-20, Kelch-like-20; MAZ, myc-associated zinc finger protein; PARP-1, poly ADP-ribose and polymerase-1; PTEN, phosphatase and tensin homolog; Sirt1, sirtuin 1; Ub, ubiquitin; USF-2, upstream stimulating factor-2; UTR, untranslated region; YY-1, yin yang-1.

Figure 3

Intestinal iron absorption. (a) Normal systemic iron levels increase circulating hepcidin levels, which degrades ferroportin (FPN). (b) Low systemic iron or anemia decreases hepcidin levels, resulting in stabilization of FPN. Also, HIF-2α stabilization in the intestine leads to transcriptional increases in divalent metal transporter-1 (DMT-1), duodenal ferric reductase (DcytB), and FPN. Other abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; HIF-2α, hypoxia-inducible factor-2α.

Figure 4

The role of hypoxia-inducible factor (HIF)-1α and HIF-2α in inflammatory bowel disease. HIF-1α activation in the intestine increases barrier-protective genes such as those encoding multidrug resistance 1a (Mdr1a), 5′-ectonucleotidase (Cd73), mucin, trefoil factor 1 (TFF1), and claudin 1 (Cldn1) and activates a protective innate immune response. HIF-2α activation in the intestine induces proinflammatory mediators such as tumor necrosis factor α (TNFα), cyclooxygenase 2 (COX2), and microsomal prostaglandin synthase 1 (mPGES1). The hypoxic response is initiated and/or maintained by cross talk with the microbiota and transmigrating immune cells (represented by dotted arrowed lines).