Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
Genes Dev. 2010 Jul 1;24(13):1403-17. doi: 10.1101/gad.1901210.
The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD(+)-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.
固醇调节元件结合蛋白 (SREBP) 转录因子家族是真核生物脂质和固醇稳态的关键调节因子。在哺乳动物中，SREBPs 在进食状态下非常活跃，可促进脂肪生成和胆固醇生成基因的表达，并促进脂肪储存。在禁食期间，小鼠肝脏中 SREBP 依赖性脂质/胆固醇合成迅速减少；然而，其机制仍不完全清楚。此外，SREBP 依赖性基因表达程序和脂质稳态控制的禁食调节在进化上的保守性也不清楚。我们在此证明，在后生动物中，NAD(+)-依赖性去乙酰化酶 SIRT1 的同源物在禁食期间下调 SREBP 同源物中具有保守作用，导致脂质合成和脂肪储存受到抑制。我们的数据表明，SIRT1 可以直接去乙酰化 SREBP，并且 SIRT1 活性的调节导致 SREBP 泛素化、蛋白稳定性和靶基因表达的改变。此外，SIRT1 的化学激活剂可在体外和体内抑制 SREBP 靶基因的表达，与肝脂质和胆固醇水平降低以及饮食诱导和遗传性肥胖小鼠的肝脂肪变性减轻相关。我们得出结论，SIRT1 同源物在控制 SREBP 依赖性基因调节方面发挥着关键作用，这些基因调节控制着后生动物对禁食信号的脂质/胆固醇稳态。这些发现可能对治疗与异常脂质/胆固醇稳态相关的代谢紊乱（包括代谢综合征和动脉粥样硬化）具有重要的生物医学意义。
