Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice.
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.
Li
Jianguo
J
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
Grigoryev
Dmitry N
DN
Ye
Shui Qing
SQ
Thorne
Laura
L
Schwartz
Alan R
AR
Smith
Philip L
PL
O'Donnell
Christopher P
CP
Polotsky
Vsevolod Y
VY
D000818:Animals; D002908:Chronic Disease; D005234:Fatty Liver / Q000378:metabolism* / Q000503:physiopathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D008055:Lipids / Q000096:biosynthesis / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D020181:Sleep Apnea, Obstructive / Q000378:metabolism* / Q000503:physiopathology*; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
D008055:Lipids; D051779:Sterol Regulatory Element Binding Proteins