Role of HIF-1α in Alcohol-Mediated Multiple Organ Dysfunction

Abstract

Excess alcohol consumption is a global crisis contributing to over 3 million alcohol-related deaths per year worldwide and economic costs exceeding $200 billion dollars, which include productivity losses, healthcare, and other effects (e.g., property damages). Both clinical and experimental models have shown that excessive alcohol consumption results in multiple organ injury. Although alcohol metabolism occurs primarily in the liver, alcohol exposure can lead to pathophysiological conditions in multiple organs and tissues, including the brain, lungs, adipose, liver, and intestines. Understanding the mechanisms by which alcohol-mediated organ dysfunction occurs could help to identify new therapeutic approaches to mitigate the detrimental effects of alcohol misuse. Hypoxia-inducible factor (HIF)-1 is a transcription factor comprised of HIF-1α and HIF-1β subunits that play a critical role in alcohol-mediated organ dysfunction. This review provides a comprehensive analysis of recent studies examining the relationship between HIF-1α and alcohol consumption as it relates to multiple organ injury and potential therapies to mitigate alcohol’s effects.

Protective effects of PX478 on gut barrier in a mouse model of ethanol and burn injury

“…HIF‐1α has conflicting roles within the body. Some studies support the beneficial effects of HIF‐1α, 44,45 whereas others have shown that it is detrimental 23,24,32,44 . Yun et al.…”

“…Some studies support the beneficial effects of HIF-1 , 44,45 whereas others have shown that it is detrimental. 23,24,32,44 Yun et al observed that inhibition of HIF-1 via PX-478 following binge ethanol exposure decreased levels of 3-nitrotyrosine and apoptosis in hepatocytes. 32 Studies have also demonstrated that large burn injury significantly elevated HIF-1 in the gut while reducing expression of tight junction proteins.…”

Transcriptomic‐based toxicological investigations of ethanol to human umbilical vein endothelial cells

“…Treatment with 5‐mM ethanol significantly altered GO term T cell mediated immunity (GO:0002456, p = 0.000877), whereas treatment with 50‐mM ethanol significantly altered GO term negative regulation of activated T cell proliferation (GO:0046007, p = 0.0014). Another example is HIF‐1 signaling pathway (ko04066), because it has been suggested that hypoxia‐inducible factor 1 (HIF‐1) signaling pathway is involved in ethanol‐induced multiple organ dysfunction (Morris & Yeligar, 2018). Here, the results showed that this pathway was more obviously altered by 5‐mM ethanol ( p = 0.066) compared with 50‐mM ethanol ( p = 0.32; Figure 4 and Tables S7 and S8).…”

The role of hypoxia‐inducible factor 1‐alpha in inflammatory bowel disease

“…PHDs use the substrates oxygen and iron as cofactors which lead to hydroxylation of the prolines on HIF‐1α, resulting in HIF‐1α ubiquitination by a von Hippel Lindau E3 ubiquitin ligase (VHL) and its subsequent degradation (Gabryelska et al, 2020). In addition to this oxygen‐dependent regulation of HIF‐1α stabilization, there are also oxygen‐independent mechanisms of HIF‐1α stabilization by reactive oxygen species (ROS) and inflammatory mediators (Morris & Yeligar, 2018).…”