Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver
Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver
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DOI：
10.1128/mcb.00006-17
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发表时间：
2017-08-01
影响因子：
5.3
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
--
作者：
Choi, Sung E.;Kwon, Sanghoon;Kemper, Jongsook Kim
Sirtuin 1（SIRT 1）去乙酰化酶延缓和改善许多肥胖相关疾病，包括非酒精性脂肪肝（NAFLD）和糖尿病，作为药物靶点受到极大关注。SIRT 1功能在肥胖症中异常低下，因此了解其潜在机制对药物开发至关重要。在这里，我们表明与肥胖相关的SIRT 1磷酸化抑制了其功能并促进了NAFLD的病理症状。在蛋白质组学分析中，Ser-164被确定为肥胖小鼠SIRT 1中的主要丝氨酸磷酸化位点，而非瘦小鼠，并且这种磷酸化由酪蛋白激酶2（CK 2）催化，其水平在肥胖中显著升高。从机制上讲，SIRT 1在Ser-164的磷酸化基本上抑制了其核定位，并适度影响其脱乙酰酶活性。在饮食诱导的肥胖小鼠中，腺病毒介导的SIRT 1或磷酸缺陷型S164 A-SIRT 1突变体的肝脏特异性表达促进了脂肪酸氧化，改善了肝脏脂肪变性和葡萄糖耐受不良，但在表达磷酸模拟物S164 D-SIRT 1突变体的小鼠中没有观察到这些有益效果。值得注意的是，磷酸化S164-SIRT 1和CK 2水平在NAFLD患者的肝脏样本中也高度升高，并与疾病严重程度相关。因此，CK 2抑制SIRT 1磷酸化可能成为治疗NAFLD和其他肥胖相关疾病的新治疗方法。
Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase 2 (CK2), the levels of which were dramatically elevated in obesity. Mechanistically, phosphorylation of SIRT1 at Ser-164 substantially inhibited its nuclear localization and modestly affected its deacetylase activity. Adenovirus-mediated liver-specific expression of SIRT1 or a phosphor-defective S164A-SIRT1 mutant promoted fatty acid oxidation and ameliorated liver steatosis and glucose intolerance in diet-induced obese mice, but these beneficial effects were not observed in mice expressing a phosphor-mimic S164D-SIRT1 mutant. Remarkably, phosphorylated S164-SIRT1 and CK2 levels were also highly elevated in liver samples of NAFLD patients and correlated with disease severity. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases.