Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1
Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1
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DOI：
10.1073/pnas.0702509104
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发表时间：
2007-07-31
影响因子：
11.1
通讯作者：
Puigserver, Pere
中科院分区：
文献类型：
--
作者：
Rodgers, Joseph T.;Puigserver, Pere
在禁食状态下，诱导肝脏葡萄糖输出和脂肪酸氧化对于维持能量平衡至关重要。肝脏对葡萄糖和脂肪酸的产生和氧化是通过复杂的转录调节因子网络控制的。其中，转录辅激活因子PGC-1 α在肝脏和全身葡萄糖和脂质代谢中起重要作用。我们以前已经证明，sirtuin 1（SIRT 1）通过相互作用和PGC-1 α的脱乙酰化来调节参与胚胎发生的基因。在这里，我们在体内表明，肝脏SIRT 1是全身和肝脏葡萄糖，脂质和胆固醇稳态的一个因素。肝脏中SIRT 1的敲低引起轻度低血糖，增加全身葡萄糖和胰岛素敏感性，并减少葡萄糖产生。SIRT 1基因敲除还降低血清胆固醇，增加肝脏游离脂肪酸和胆固醇含量。SIRT 1基因敲低引起的这些代谢表型与致炎基因、脂肪酸氧化和胆固醇降解基因以及外排基因的表达降低密切相关。此外，SIRT 1的过表达逆转了SIRT 1敲低引起的许多变化，并依赖于PGC-1 α的存在。有趣的是，SIRT 1的大部分作用仅在禁食状态下明显。我们的研究结果表明，肝脏SIRT 1是一个重要的因素，在调节葡萄糖和脂质代谢的营养剥夺。由于这些途径在代谢疾病中失调，SIRT 1可能是控制高血糖和高胆固醇血症的潜在治疗靶点。
In the fasted state, induction of hepatic glucose output and fatty acid oxidation is essential to sustain energetic balance. Production and oxidation of glucose and fatty acids by the liver are controlled through a complex network of transcriptional regulators. Among them, the transcriptional coactivator PGC-1 alpha plays an important role in hepatic and systemic glucose and lipid metabolism. We have previously demonstrated that sirtuin 1 (SIRT1) regulates genes involved in gluconeogenesis through interaction and deacetylation of PGC-1 alpha. Here, we show in vivo that hepatic SIRT1 is a factor in systemic and hepatic glucose, lipid, and cholesterol homeostasis. Knockdown of SIRT1 in liver caused mild hypoglycemia, increased systemic glucose and insulin sensitivity, and decreased glucose production. SIRT1 knockdown also decreased serum cholesterol and increased hepatic free fatty acid and cholesterol content. These metabolic phenotypes caused by SIRT1 knockdown tightly correlated with decreased expression of gluconeogenic, fatty acid oxidation and cholesterol degradation as well as efflux genes. Additionally, overexpression of SIRT1 reversed many of the changes caused by SIRT1 knockdown and depended on the presence of PGC-1 alpha. Interestingly, most of the effects of SIRT1 were only apparent in the fasted state. Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation. As these pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target to control hyperglycemia and hypercholesterolemia.