Enhanced acetylation of ATP-citrate lyase promotes the progression of nonalcoholic fatty liver disease
Enhanced acetylation of ATP-citrate lyase promotes the progression of nonalcoholic fatty liver disease
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ATP-柠檬酸裂解酶的乙酰化增强促进非酒精性脂肪肝的进展
DOI：
10.1074/jbc.ra119.008708
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发表时间：
2019-08-02
影响因子：
4.8
通讯作者：
Tang, Qi-Qun
中科院分区：
文献类型：
--
作者：
Guo, Liang;Guo, Ying-Ying;Tang, Qi-Qun
肝脂肪变性是非酒精性脂肪性肝病（NAFLD）的一个标志，由脂肪生成失调促进。atp -柠檬酸裂解酶（ACLY）是一种重要的脂肪生成酶，在NAFLD患者中上调。先前的研究表明，ACLY在Lys-540、Lys-546和Lys-554位点（ACLY- 3k）的乙酰化通过拮抗其泛素化而增加ACLY蛋白的稳定性，从而促进肺癌细胞的脂质合成和细胞增殖。但这种调节机制在其他细胞或组织环境或其他病理生理条件下的功能重要性有待进一步研究。在这里，我们发现ACLY- 3k乙酰化也促进了小鼠肝细胞系AML12细胞中ACLY蛋白的稳定性，并发现去乙酰化酶sirtuin 2 （SIRT2）使ACLY- 3k去乙酰化并使这些细胞中的ACLY不稳定。值得注意的是，患有NAFLD的小鼠和人的肝脏中ACLY蛋白和ACLY- 3k乙酰化水平升高，SIRT2蛋白水平降低。通过用三种谷氨酰胺（ACLY-3KQ变体）代替三种赖氨酸来模拟ACLY-3K乙酰化，促进了高糖处理的AML12细胞和高脂/高糖（HF/HS）饮食喂养小鼠肝脏中的脂质积累。此外，在AML12细胞中过表达SIRT2抑制脂质积累，而过表达ACLY- 3kq变体比过表达WT ACLY变体更有效地逆转脂质积累。此外，肝脏SIRT2过表达降低了HF/HS日粮喂养小鼠的ACLY-3K乙酰化及其蛋白水平，减轻了肝脏脂肪变性。我们的研究结果揭示了NAFLD中肝脏ACLY上调的转录后机制，并表明SIRT2/ACLY轴参与NAFLD的进展。
Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and is promoted by dysregulated de novo lipogenesis. ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that is up-regulated in individuals with NAFLD. A previous study has shown that acetylation of ACLY at Lys-540, Lys-546, and Lys-554 (ACLY-3K) increases ACLY protein stability by antagonizing its ubiquitylation, thereby promoting lipid synthesis and cell proliferation in lung cancer cells. But the functional importance of this regulatory mechanism in other cellular or tissue contexts or under other pathophysiological conditions awaits further investigation. Here, we show that ACLY-3K acetylation also promotes ACLY protein stability in AML12 cells, a mouse hepatocyte cell line, and found that the deacetylase sirtuin 2 (SIRT2) deacetylates ACLY-3K and destabilizes ACLY in these cells. Of note, the livers of mice and humans with NAFLD had increased ACLY protein and ACLY-3K acetylation levels and decreased SIRT2 protein levels. Mimicking ACLY-3K acetylation by replacing the three lysines with three glutamines (ACLY-3KQ variant) promoted lipid accumulation both in high glucose–treated AML12 cells and in the livers of high-fat/high-sucrose (HF/HS) diet–fed mice. Moreover, overexpressing SIRT2 in AML12 cells inhibited lipid accumulation, which was more efficiently reversed by overexpressing the ACLY-3KQ variant than by overexpressing WT ACLY. Additionally, hepatic SIRT2 overexpression decreased ACLY-3K acetylation and its protein level and alleviated hepatic steatosis in HF/HS diet–fed mice. Our findings reveal a posttranscriptional mechanism underlying the up-regulation of hepatic ACLY in NAFLD and suggest that the SIRT2/ACLY axis is involved in NAFLD progression.