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1 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
2 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, none
* To whom correspondence should be addressed. E-mail: vpolots1{at}jhmi.edu.
Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin deficient obese ob/ob mice were subjected to CIH during the light phase (9 am-9 pm) for 12 weeks. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with subsequent real time PCR validation) were determined upon completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (p < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH up-regulated multiple genes controlling: (1) both cholesterol and fatty acid biosynthesis (malic enzyme, acetyl-CoA synthetase); (2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase, stearoyl-CoA desaturases 1 and 2); (3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol 3- phosphate acyltransferase). A majority of over-expressed genes were transcriptionally regulated by sterol regulatory element binding protein 1 (SREBP-1), a master-regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (p = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate pre-existing fatty liver of obesity via up-regulation of the pathways of lipid biosynthesis in the liver.
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