Endocrine targets of hypoxia-inducible factors

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   Figure 1

   Schematic drawings show domain structure and regulation of HIFs. (A) Protein domain structures of HIF family members. Basic helix-loop-helix (H) domain is for DNA binding and Per-Arnt-Sim (PAS) domain is for dimerization. HIF-α contains oxygen-dependent degradation domain (O), which regulates HIF-α stability through the hydroxylation of proline (P) residues. HIF-1α and HIF-2α contain two transactivation domains (T), N-TAD and C-TAD. The asparagine (N) residue is another amino acid that can be hydroxylated. The total length of each subunit is marked at the end of the domain structure. (B) Under normal oxygen tension, HIF-α subunit is hydroxylated by PHD, the hydroxylated proline residues is recognized and ubiquitylated by VHL and its associated ubiquitin ligase complex. Polyubiquitylated HIF-α subunit causes the protein degradation. HIF-α subunit binding with transcriptional co-activator p300/CBP complex is also inhibited by hydroxylation of asparagine residue by FIH. Under hypoxia, the enzymatic activity of PHDs and FIH are decreased. Therefore, HIF-α subunit escapes the degradation and associates with HIF-β and the transcriptional co-activator in the nucleus. The heterodimer of HIF binds to consensus sequence HRE at the promoter region of HIF-responsive genes, such as VEGF and EPO, and initiates the gene transcription.
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   Figure 2

   Regulation and function of HIF in endocrine organs associated with type 2 diabetes mellitus. (A) The effects of HIF signaling on glucose and lipid metabolism are more ambiguous, but there appears some link between hypoxia and T2DM development. The process of glucose metabolism consumes robust oxygen; thus, β-cells encounter cellular hypoxia condition that activates HIF-1/2α. Mice with β-cell-specific knockout Hif-1α, Hif-1β, or Vhl knockout show the impaired glucose metabolism features. (B) Adipose tissue expansion in obesity causes the hypoxic microenvironment. Hypoxia activates the HIF-1α and HIF-2α cascades. HIF-1α increases adipose tissue fibrosis by upregulating collagen expression and promoting the crosslinking of collagens, which ultimately results in inflammation and insulin resistance. Conversely, HIF-2α has protective effect through opposing the HIF-1α pathway. Besides, HIF-2α induces angiogenesis, which improves the oxygen level of adipose. (C) Hepatic lipid metabolism is a component of T2DM. Hypoxic hepatocytes, such as those in pericentral zone, are more involved in lipogenesis and repression of β-oxidation. In experimental obesity models, intermittent hypoxia exposure worsens the insulin intolerance and hepatic steatosis. Hepatocyte-specific Hif-1α knockout mice fed with high-fat diet exhibit glucose intolerance. Hepatic ablation of Hif-1β in mice increases the hepatic glucose production and impairs the glucose tolerance.
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   Figure 3

   Hypoxia is involved in pathological processes of endometriosis. Retrograded endometrial fragments suffer from hypoxia before the vascular growth. Hypoxic condition stimulates prostaglandin-E₂ (PGE₂) production in ectopic cell by repression of dual-specificity phosphatase-2 (DUSP2) and induction of miR20-a. Activation of ERK further promotes angiogenesis by induction of angiogenic factors, such as, Cysteine-rich angiogenic inducer 61 (CYR61), osteopontin (OPN) and interleukin-8 (IL-8). Hypoxia induces leptin (LEP) and miR210 expression and thus promotes ectopic cell proliferation and autophagy/cell viability. In addition, hypoxia inhibits the migration inhibitor CD26/dipeptidyl peptidase IV (CD26/DPPIV) expression that increases the ability of cell migration.
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   Figure 4

   HIF expression levels and systemic effects of endocrine gland tumor. (A) A summary of disorders caused by endocrine tumors. The imbalance of hormone secretion due to endocrine glands tumors usually leads to alteration of physiological functions due to the complex feedback mechanisms of hormone. As a result, whole body homeostasis is disturbed and symptoms occur. (B) The levels of HIFs are correlated with the clinical observation in different types of endocrine tumors. PET, pancreatic endocrine tumor.

• © 2017 Society for Endocrinology