Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; and 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Submitted 3 May 2...

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Published in:Journal of applied physiology (1985) 2005-11, Vol.99 (5), p.1643-1648
Main Authors: Li, Jianguo, Grigoryev, Dmitry N, Ye, Shui Qing, Thorne, Laura, Schwartz, Alan R, Smith, Philip L, O'Donnell, Christopher P, Polotsky, Vsevolod Y
Format: Article
Language:English
Subjects:
Animals
Chronic Disease
Fatty acids
Fatty Liver - metabolism
Fatty Liver - physiopathology
Gene expression
Gene Expression Profiling
Gene Expression Regulation - physiology
Homeostasis - physiology
Hypoxia - metabolism
Hypoxia - physiopathology
Lipids - biosynthesis
Lipids - blood
Liver
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Obesity
Obesity - metabolism
Obesity - physiopathology
Rodents
Sleep Apnea, Obstructive - metabolism
Sleep Apnea, Obstructive - physiopathology
Sleep disorders
Sterol Regulatory Element Binding Proteins - genetics
Sterol Regulatory Element Binding Proteins - metabolism
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Summary:1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; and 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Submitted 3 May 2005 ; accepted in final form 18 July 2005 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 exposed to CIH during the light phase (9 AM–9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on 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 upregulated multiple genes controlling 1 ) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2 ) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3 ) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (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-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver. obstructive sleep apnea; fatty liver; mouse; gene expression Address for reprint requests and other correspondence: V. Y. Polotsky, Div. of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail: vpolots1{at}jhmi.edu )
ISSN:8750-7587
1522-1601
DOI:10.1152/japplphysiol.00522.2005