Li Jianguo, Grigoryev Dmitry N, Ye Shui Qing, Thorne Laura, Schwartz Alan R, Smith Philip L, O'Donnell Christopher P, Polotsky Vsevolod Y
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
J Appl Physiol (1985). 2005 Nov;99(5):1643-8. doi: 10.1152/japplphysiol.00522.2005. Epub 2005 Jul 21.
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.
阻塞性睡眠呼吸暂停（OSA）与肥胖密切相关，可导致睡眠期间慢性间歇性缺氧（CIH）。越来越多的证据表明，OSA与胰岛素抵抗和脂肪性肝病独立相关，提示OSA可能影响肝脏脂质代谢。为验证这一假设，在光照期（上午9点至晚上9点）将瘦素缺乏的肥胖（ob/ob）小鼠暴露于CIH环境中12周。暴露结束后，测定肝脏脂质含量和肝脏基因表达谱（采用Affymetrix 430基因芯片并经实时PCR验证）。CIH使肝脏甘油三酯和磷脂含量增加30%（P<0.05），而肝脏胆固醇含量未变。基因表达分析显示，CIH上调了多个控制以下方面的基因：1）胆固醇和脂肪酸生物合成[苹果酸酶和乙酰辅酶A（CoA）合成酶]；2）主要是脂肪酸生物合成（乙酰辅酶A羧化酶和硬脂酰辅酶A去饱和酶1和2）；3）甘油三酯和磷脂生物合成（线粒体甘油-3-磷酸酰基转移酶）。大多数过表达基因受脂质生成的主要调节因子固醇调节元件结合蛋白（SREBP）1转录调控。实时PCR证实CIH中SREBP-1基因表达增加2.8倍（P = 0.001）。胆固醇生物合成的主要基因SREBP-2和3-羟基-3-甲基戊二酰辅酶A还原酶的表达未变。总之，我们已表明，CIH可能通过上调肝脏脂质生物合成途径而加重肥胖患者已有的脂肪肝。
