Mechanisms of Liver Fibrosis in OSA
2017 Physician Scientist Training Grant
Omar Mesarwi, MD
University of California, San Diego
Key Project Outcomes
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia—reductions in oxygen saturation that arise due to recurrent collapse of the upper airway during sleep. OSA is highly prevalent and underdiagnosed, and leads to daytime sleepiness and disturbed sleep. However, several studies have shown that OSA is also associated with a variety of adverse health outcomes which may be less well-noticed by those afflicted. For instance, patients with OSA are more likely to have cardiovascular disease, mood disorders, and cognitive dysfunction. Recent evidence has shown that OSA is associated with metabolic dysfunction as well, specifically, a higher risk for insulin resistance and diabetes, and nonalcoholic fatty liver disease (NAFLD). This proposal aimed to identify how OSA may cause NAFLD. NAFLD is the most common disease of the liver, and results from obesity and insulin resistance. Patients with NAFLD may develop cirrhosis or other complications of their liver disease and can result in a need for liver transplant or liver-related death. Finding the precise ways in which patients with OSA are at increased risk for NAFLD could lead to the promise of therapies targeting specific molecular pathways in these individuals and could also lead to earlier testing and referral to specialized centers.
The intermittent hypoxia of OSA impairs glucose tolerance and insulin resistance in mouse models of this disorder. Intermittent hypoxia also appears to worsen liver steatosis and fibrosis, two major histologic markers of liver injury in NAFLD. Liver fibrosis in particular is the principal marker of worsened patient outcomes. The ways in which hypoxia may worsen liver injury are not well defined. Obesity in mice causes fatty liver, which in turn leads to liver tissue hypoxia, and this is substantially worsened in models of superimposed intermittent hypoxia. Moreover, this liver tissue hypoxia leads to an increase in hepatic HIF-1α levels. HIF-1 is a cellular regulator of the response to hypoxia. Disruption of HIF-1 signaling in mice attenuates the metabolic consequences of a high fat diet, causing weight reduction, a shift in the metabolic profile toward fat oxidation, and a reduction in fasting glucose and insulin levels.
The work supported by this grant has extended this understanding of the link between intermittent hypoxia and liver damage via HIF-1 signaling. We have shown that HIF-1 is a key regulator of liver fibrosis in a mouse model of NAFLD: Knockout of HIF-1α in hepatocytes reduces liver fibrosis and leads to substantial changes in hepatic expression of several genes related to fatty acid metabolism. Through whole transcriptome shotgun sequencing, we have identified key metabolic pathways which are divergent in mice with HIF-1α knockout. Additionally, we have shown that glucose dysregulation in intermittent hypoxia is related to hepatic mitochondrial dysfunction. These studies are still ongoing, and we continue to learn more every day about the interplay between intermittent hypoxia and liver injury.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Putting it Together: Sleep Apnea, the Integrated Stress Response, and Metabolic Dysfunction
METABOLISM CLINICAL AND EXPERIMENTAL
Sleep apnea, metabolic disease, and the cutting edge of therapy
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease