Chronic intermittent hypoxia alleviates alcohol-related liver injury via downregulation of hepatic hypoxia-inducible factor-2α.
Study Goal
The researchers aimed to investigate the relationship between alcohol-enhanced obstructive sleep apnea (OSA) and the progression of alcohol-related liver disease (ALD), focusing on the role of hypoxia-inducible factor 2α (HIF-2α).
Results Summary
Chronic intermittent hypoxia (CIH) intervention ameliorated alcohol-related liver injury, reduced hepatic lipid accumulation, oxidative stress, and inflammation in mice. Mechanistically, CIH inhibited alcohol-induced upregulation of HIF-2α, and similar effects were observed with the HIF-2α inhibitor PT2385, suggesting a potential therapeutic target for ALD.
Population
Gao-binge ALD and CIH mouse models, and LPS/ethanol-co-treated AML12 hepatocytes (in vitro).
Effective Dosage
Not specified for alcohol; PT2385 (selective HIF-2α inhibitor) was used in mice.
Duration
Not explicitly stated, but implied chronic intervention.
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
CIH intervention | decrease | alcohol-related liver injury | Gao-binge ALD and CIH mouse models | - | ameliorated | #1 |
CIH intervention | decrease | hepatic lipid accumulation | Gao-binge ALD and CIH mouse models | - | reduced | #2 |
CIH intervention | decrease | oxidative stress | Gao-binge ALD and CIH mouse models | - | reduced | #3 |
CIH intervention | decrease | liver inflammation | Gao-binge ALD and CIH mouse models | - | alleviated | #4 |
CIH intervention | decrease | alcohol-induced upregulation and activation of hypoxia-inducible factor 2α (HIF-2α) | Gao-binge mice | - | inhibited | #5 |
PT2385 | decrease | alcohol-related liver injury | Gao-binge mice | - | alleviated | #6 |
PT2385 | decrease | steatosis | Gao-binge mice | - | alleviated | #7 |
PT2385 | decrease | oxidative stress | Gao-binge mice | - | inhibiting | #8 |
PT2385 | decrease | inflammation | Gao-binge mice | - | inhibiting | #9 |
CIH | decrease | HIF-2α | AML12 cells co-challenged with LPS and ethanol | - | downregulated | #10 |
CIH | increase | calpains protein expression | AML12 cells co-challenged with LPS and ethanol | - | promoting | #11 |
CIH | decrease | accumulation of lipid droplets | AML12 cells co-challenged with LPS and ethanol | - | reducing | #12 |
CIH | decrease | ROS production | AML12 cells co-challenged with LPS and ethanol | - | decreasing | #13 |
BACKGROUND: Alcohol-related liver disease (ALD) is one of the leading causes of alcohol-related morbidity and mortality worldwide. Unfortunately, limited therapeutic options are currently available, due to the complex risk factors involved as well as the lack of information on the molecular mechanisms driving its progression. Interestingly, chronic, excessive alcohol intake has been reported to exacerbate the severity of Obstructive sleep apnea (OSA), a respiratory disorder typically characterized by chronic intermittent hypoxia (CIH). However, this relationship between alcohol-enhanced OSA and ALD development/progression remains to be elucidated. METHODS: As an approach to investigate this relationship in vivo Gao-binge ALD and CIH mouse models were established. Alcohol-related liver injury, hepatic steatosis, inflammation and oxidative stress were then assessed in these models. In addition, LPS and ethanol-co-treated AML12 hepatocytes served as an in vitro model to investigate the mechanisms through which CIH affects ethanol-induced liver injury. RESULTS: CIH intervention ameliorated alcohol-related liver injury, reduced hepatic lipid accumulation and oxidative stress and alleviated liver inflammation. Mechanistically, in the liver of these Gao-binge mice, CIH intervention inhibited alcohol-induced upregulation and activation of hypoxia-inducible factor 2α (HIF-2α), a protein which plays a key role in hepatic lipid metabolism and liver injury. Similar to these effects observed in response to CIH intervention, treatment of Gao-binge mice with the selective inhibitor of HIF-2α, PT2385, alleviated alcohol-related liver injury and steatosis while inhibiting oxidative stress and inflammation. Additional findings from our in vitro model revealed that CIH downregulated HIF-2α by promoting calpains protein expression, thereby reducing the accumulation of lipid droplets and decreasing ROS production in AML12 cells co-challenged with LPS and ethanol. CONCLUSIONS: The above results provide important, new evidence that re-conceptualizes the role of alcohol-enhanced OSA in ALD progression. Moreover, these findings can serve as the foundation for the development of HIF-2α inhibitors for use in the prevention and treatment of ALD.