Obstructive sleep apnea (OSA) leads to high cardiovascular mortality, which has been attributed to metabolic abnormalities induced by chronic intermittent hypoxia (IH). We have developed a mouse model of chronic IH, which mimics the oxygen profile in human OSA, and have shown that IH causes dyslipidemia, hepatic steatosis and insulin resistance. We have also shown that IH leads to metabolic dysfunction by stimulating a key hepatic enzyme of lipid biosynthesis, stearoyl Coenzyme A desaturase 1 (SCD-1). We accumulated evidence allowing to formulate our main hypothesis that chronic IH causes dyslipidemia and hepatic steatosis by up-regulating SCD-1 via two major pathways, (1) induction of hepatic hypoxia inducible factor 1 (HIF-1) with downstream activation of key factors of lipid biosynthesis, sterol regulatory element binding protein 1c (SREBP-1c), liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPAR?), (2) activation of the sympathetic nervous system (SNS) resulting in increased hepatic glucose output and up-regulation of carbohydrate response element-binding protein ChREBP.
In Specific Aim #1 we will examine the role of HIF-1 in metabolic dysfunction during IH. We propose that IH up-regulates SCD-1 via HIF-1 and therefore (A) IH-induced increase in hepatic SCD-1, dyslipidemia and hepatic steatosis will be attenuated in mice with HIF-1? deficient livers;(B) hypoxic up-regulation of SCD-1 will be abolished by HIF-1? deficiency in isolated hepatocytes;(C) constitutive expression of HIF-1? in mouse hepatocytes will induce SCD-1;(D) hypoxia will induce the SCD-1 promoter, this induction will be abolished by HIF-1? deficiency, and constitutively active HIF-1? will be sufficient to drive promoter activity.
In Specific Aim #2, we will determine pathways downstream of HIF-1, by which hypoxia induce SCD-1 in cultured hepatocytes. We propose that HIF-1 up-regulates SCD-1 via increased activity of LXR, PPAR? and SREBP-1c and therefore (A) SCD-1 up-regulation by hypoxia or by constitutive expression of HIF-1? will be attenuated by deficiency of LXR?/?, PPAR? and SREBP-1c and abolished by the combined deficiency of these transcription factors, (B) induction of the SCD-1 promoter by hypoxia or by constitutive expression of HIF- 1? will be attenuated by deficiency of LXR?/?, PPAR? and SREBP-1c and abolished by the combined deficiency of these transcription factors.
In Specific Aim #3, we will explore the role of ChREBP in up- regulation of hepatic SCD-1 during IH. We propose that IH acts through the SNS to induce ChREBP, which up-regulates SCD-1 leading to dyslipidemia and hepatic steatosis. We hypothesize that (A) induction of hepatic ChREBP by IH will be abolished and up-regulation of SCD-1 will be attenuated by the blockade of the SNS;(B) ChREBP deficiency will attenuate chronic IH-induced increases in hepatic SCD- 1, dyslipidemia and hepatic steatosis.
Obstructive sleep apnea increases risk of heart attack, stroke, and premature death. We hypothesize that increased cardiovascular risk in sleep apnea is related to specific molecular mechanisms, which induce elevation of serum lipids and cause fatty liver, diabetes, and atherosclerosis. We propose to use a mouse model of sleep apnea to explore these mechanisms and identify novel therapeutic targets, which may improve outcomes in patients with sleep apnea and the cardiovascular disease.
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