Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
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DOI：
10.1101/gad.1901210
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发表时间：
2010-07-01
影响因子：
10.5
通讯作者：
Naar, Anders M.
中科院分区：
文献类型：
--
作者：
Walker, Amy K.;Yang, Fajun;Naar, Anders M.
甾醇调节元件结合蛋白（SREBP）转录因子家族是真核生物脂质和甾醇稳态的关键调节因子。在哺乳动物中，SREBPs在喂养状态下高度活跃，促进脂肪生成和胆固醇生成基因的表达，促进脂肪储存。禁食期间，小鼠肝脏中依赖srebp的脂质/胆固醇合成迅速减少；然而，其机制仍未完全了解。此外，srebp依赖性基因表达和脂质稳态控制的禁食调控的进化保守性尚不清楚。我们在此证明了后生动物中NAD（+）依赖性去乙酰化酶SIRT1的同源基因在禁食期间下调SREBP同源基因中的保守作用，从而抑制脂质合成和脂肪储存。我们的数据显示SIRT1可以直接使SREBP去乙酰化，SIRT1活性的调节导致SREBP泛素化、蛋白稳定性和靶基因表达的变化。此外，SIRT1的化学激活剂在体外和体内抑制SREBP靶基因的表达，与饮食诱导和遗传性肥胖小鼠肝脏脂质和胆固醇水平的降低以及肝脏脂肪变性的减轻有关。我们得出结论，SIRT1同源物在控制srebp依赖的基因调控中发挥关键作用，调控后生动物对禁食提示的脂质/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。
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.