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The role of hypoxia-inducible factors in metabolic diseases

Nature Reviews Endocrinology volume 15, pages 21–32 (2019)Cite this article

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Abstract

Hypoxia-inducible factors (HIFs), a family of transcription factors activated by hypoxia, consist of three α-subunits (HIF1α, HIF2α and HIF3α) and one β-subunit (HIF1β), which serves as a heterodimerization partner of the HIFα subunits. HIFα subunits are stabilized from constitutive degradation by hypoxia largely through lowering the activity of the oxygen-dependent prolyl hydroxylases that hydroxylate HIFα, leading to their proteolysis. HIF1α and HIF2α are expressed in different tissues and regulate target genes involved in angiogenesis, cell proliferation and inflammation, and their expression is associated with different disease states. HIFs have been widely studied because of their involvement in cancer, and HIF2α-specific inhibitors are being investigated in clinical trials for the treatment of kidney cancer. Although cancer has been the major focus of research on HIF, evidence has emerged that this pathway has a major role in the control of metabolism and influences metabolic diseases such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Notably increased HIF1α and HIF2α signalling in adipose tissue and small intestine, respectively, promotes metabolic diseases in diet-induced disease models. Inhibition of HIF1α and HIF2α decreases the adverse diet-induced metabolic phenotypes, suggesting that they could be drug targets for the treatment of metabolic diseases.

Key points

  • Obesity triggers hypoxia in adipose tissue and the small intestine, which stabilizes and activates hypoxia-inducible factor (HIF)1α and HIF2α signalling, resulting in adverse metabolic effects, including insulin resistance and non-alcoholic fatty liver disease.

  • Induction of HIF1α in adipocytes, through a suppressor of cytokine signalling 3 (SOCS3)–signal transducer and activator of transcription 3 (STAT3) axis, leads to the upregulation of inflammation and downregulation of adiponectin expression, resulting in insulin resistance.

  • Activation of HIF2α in the small intestine increases expression of sialidase 3, resulting in an elevation of small intestinal and serum levels of ceramides that in turn potentiate obesity-associated metabolic diseases.

  • Genetic or chemical inhibition of HIF1α and HIF2α signalling in adipose tissue and the small intestine ameliorates obesity-associated metabolic diseases, indicating that they could be targeted for treatment of metabolic disorders.

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Fig. 1: Hypoxia-inducible factor-α proteins are hydroxylated under normoxic conditions by prolyl hydroxylase domain enzymes.
Fig. 2: Hypoxia-inducible factor 1α in adipose tissue.
Fig. 3: Hypoxia-inducible factor 2α in liver glucose metabolism.
Fig. 4: Hypoxia-inducible factor 2α in metabolic disease.

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Acknowledgements

The authors acknowledge the support of the National Cancer Institute Intramural Research Program, the NIH, the National Key Research and Development Program of China (2016YFC0903100), the National Natural Science Foundation of the People’s Republic of China (81522007, 81470554 and 31401011) and the Fundamental Research Funds for the Central Universities: Clinical Medicine Plus X–Young Scholars Project of Peking University (PKU2018LCXQ013).

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Authors and Affiliations

  1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    Frank J. Gonzalez & Cen Xie

  2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China

    Changtao Jiang

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  1. Frank J. Gonzalez
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F.J.G. and C.J. researched the data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. C.X. reviewed and/or edited the manuscript before submission.

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Correspondence to Frank J. Gonzalez or Changtao Jiang.

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Gonzalez, F.J., Xie, C. & Jiang, C. The role of hypoxia-inducible factors in metabolic diseases. Nat Rev Endocrinol 15, 21–32 (2019). https://doi.org/10.1038/s41574-018-0096-z

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