Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice
Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice
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DOI：
10.1152/japplphysiol.00522.2005
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发表时间：
2005-11-01
影响因子：
3.3
通讯作者：
Polotsky, VY
中科院分区：
文献类型：
--
作者：
Li, JG;Grigoryev, DN;Polotsky, VY
阻塞性睡眠呼吸暂停（OSA）是一种与肥胖密切相关的疾病，会导致睡眠期间的慢性间歇性缺氧（CIH）。有证据表明OSA与胰岛素抵抗和脂肪肝独立相关，提示OSA可能影响肝脏脂质代谢。为了验证这一假设，瘦素缺乏的肥胖（ob/ob）小鼠暴露于CIH在光相（上午9点至下午9点）12周。暴露完成后，测定肝脏脂质含量和肝脏基因表达谱（Affymetrix 430 GeneChip，具有实时PCR验证）。CIH使肝脏甘油三酯和磷脂含量增加30%（P < 0.05），而肝脏胆固醇含量无变化。基因表达分析表明，CIH上调多个基因控制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），和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）。大多数过表达基因的转录调控固醇调节元件结合蛋白（SREBP）1，脂肪生成的主调节器。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还原酶的表达没有变化。总之，我们已经表明，CIH可能通过上调肝脏中的脂质生物合成途径而加重肥胖性脂肪肝。
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.