Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

Fábián, Zsolt; Taylor, Cormac T.; Nguyen, Lan K.

doi:10.1007/s00109-016-1383-6

Cited by 20 publications

(16 citation statements)

References 103 publications

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“…in the presence of oxygen and ROS; the interested reader is referred to a number of reviews covering that topic in more detail [61], [62], [63], [64], [65], [66]. In brief, heavy metals, hormones such as insulin, growth and coagulation factors such as HGF, IGF, thrombin, cytokines such as TNFα, lipopolysaccharides (LPS), and mechanical stress have been shown to contribute to that regulation by involving one or more intracellular signaling pathways such as the phosphatidylinositol-3-kinase (PI3K) protein kinase B/Akt, the mTOR, p70S6K1, and RAS/RAF/ERK1/2 as well as mitochondrial metabolites such as the PHD/FIH substrate α-ketoglutarate [65].…”

Section: Hypoxia-inducible Transcription Factors (Hifs)mentioning

confidence: 99%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

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Section: Hypoxia-inducible Transcription Factors (Hifs)mentioning

confidence: 99%

Metabolic zonation of the liver: The oxygen gradient revisited

2017

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“…The molecular mechanisms involved in the response to hypoxia at the cellular level are relatively well understood (Fábián et al, 2016 ; Bhattarai et al, 2017 ; Koyasu et al, 2017 ). However, the complexity of the interactions between the divergent signaling pathways and the time frame of the various processes on different tissues and organs, together with the significant individual variability in humans' susceptibility to hypoxia (Rathat et al, 1992 ), pose formidable challenges to researching the potential benefits of regular programs involving exposure to real or simulated altitudes.…”

Section: Biological Effects Of Intermittent Hypoxia Exposurementioning

confidence: 99%

Physiological and Biological Responses to Short-Term Intermittent Hypobaric Hypoxia Exposure: From Sports and Mountain Medicine to New Biomedical Applications

et al. 2018

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In recent years, the altitude acclimatization responses elicited by short-term intermittent exposure to hypoxia have been subject to renewed attention. The main goal of short-term intermittent hypobaric hypoxia exposure programs was originally to improve the aerobic capacity of athletes or to accelerate the altitude acclimatization response in alpinists, since such programs induce an increase in erythrocyte mass. Several model programs of intermittent exposure to hypoxia have presented efficiency with respect to this goal, without any of the inconveniences or negative consequences associated with permanent stays at moderate or high altitudes. Artificial intermittent exposure to normobaric hypoxia systems have seen a rapid rise in popularity among recreational and professional athletes, not only due to their unbeatable cost/efficiency ratio, but also because they help prevent common inconveniences associated with high-altitude stays such as social isolation, nutritional limitations, and other minor health and comfort-related annoyances. Today, intermittent exposure to hypobaric hypoxia is known to elicit other physiological response types in several organs and body systems. These responses range from alterations in the ventilatory pattern to modulation of the mitochondrial function. The central role played by hypoxia-inducible factor (HIF) in activating a signaling molecular cascade after hypoxia exposure is well known. Among these targets, several growth factors that upregulate the capillary bed by inducing angiogenesis and promoting oxidative metabolism merit special attention. Applying intermittent hypobaric hypoxia to promote the action of some molecules, such as angiogenic factors, could improve repair and recovery in many tissue types. This article uses a comprehensive approach to examine data obtained in recent years. We consider evidence collected from different tissues, including myocardial capillarization, skeletal muscle fiber types and fiber size changes induced by intermittent hypoxia exposure, and discuss the evidence that points to beneficial interventions in applied fields such as sport science. Short-term intermittent hypoxia may not only be useful for healthy people, but could also be considered a promising tool to be applied, with due caution, to some pathophysiological states.

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“…The complexity of these interactions make the crosstalk between hypoxia and inflammatory pathways an attractive topic for developing a systems biology approach to advance our understanding of the temporal and dynamic aspects of this relationship (98).…”

Section: Hydroxylase-independent Pathways Activated In Hypoxiamentioning

confidence: 99%