Grant: Project Grant

Sleep apnea is a common respiratory disorder occurring as the airflow to the lungs is obstructed by the closure of the airways. During obstructions, oxygen levels in the blood drop then abruptly return to normal as breathing starts again. This pattern of blood oxygen swings (called "Intermittent Hypoxia"), that can be repeated throughout the night, induces many other diseases including hypertension and metabolic disorders such as diabetes. A common complication of diabetes known as "fatty liver disease" (a pathological accumulation of fat in the liver) is also commonly associated with sleep apnea. Interestingly the prevalence and severity of sleep apnea and fatty liver disease are different between men and women (with men at greater risks), and these differences are still poorly understood. Researchers have successfully created animal models that simulate the intermittent hypoxia during sleep and these are extremely useful to explore the mechanisms underlying the links with specific diseases. By using such models, we have uncovered a striking pattern of gene expression in the liver, showing a particularly strong induction of "FMO" (or "Flavin-containing monooxygenase") in male mice exposed to IH. The expression of this gene is normally repressed by testosterone secretion in males compared to females, it is thus particularly intriguing that much stronger effects of hypoxia were apparent in castrated male mice. New roles of FMO against a variety of liver injuries have been recently described, therefore our hypothesis is that high expression of FMO in the liver prevents important dysfunction in female mice. We will use male and female mice to describe the expression pattern of FMO enzymes in the liver under conditions that mimic different severity of sleep apnea and nutritional status (lean or obese) associated with these diseases, measure associated liver damage, and use mice with selective deletion or induction of these genes to assess their roles.