The protein acetylase GCN5L1 modulates hepatic fatty acid oxidation activity via acetylation of the mitochondrial β-oxidation enzyme HADHA.
The protein acetylase GCN5L1 modulates hepatic fatty acid oxidation activity via acetylation of the mitochondrial β-oxidation enzyme HADHA.
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DOI：
10.1074/jbc.ac118.005462
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发表时间：
2018-11-16
期刊：
影响因子：
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通讯作者：
Scott I
中科院分区：
文献类型：
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作者：
Thapa D;Wu K;Stoner MW;Xie B;Zhang M;Manning JR;Lu Z;Li JH;Chen Y;Gucek M;Playford MP;Mehta NN;Harmon D;O'Doherty RM;Jurczak MJ;Sack MN;Scott I
Sirtuin 3 (SIRT3) 脱乙酰并激活肝脏中的几种线粒体脂肪酸氧化酶。在这里，我们研究了蛋白质乙酰化酶 GCN5 一般控制氨基酸合成 5-like 1 (GCN5L1) 是否参与肝脏脂肪酸氧化的调节，此前已证明该酶可对抗 SIRT3 活性。我们发现 GCN5L1 丰度因急性高脂肪饮食 (HFD) 而显着上调。转基因 GCN5L1 在小鼠肝脏中的过度表达增加了蛋白质乙酰化水平，并且对特定赖氨酸残基的蛋白质组学检测发现了许多由 GCN5L1 和 SIRT3 共同调节的位点。我们分析了通过蛋白质组筛选鉴定的几种脂肪酸氧化蛋白，发现羟酰辅酶A脱氢酶三功能多酶复合物亚基α (HADHA) 的过度乙酰化与GCN5L1水平升高相关。 HepG2 细胞中稳定的 GCN5L1 敲低可减少 HADHA 乙酰化并增加脂肪酸氧化酶的活性。与 WT 对照相比，肝脏特异性删除 GCN5L1 的小鼠在慢性 HFD 后不会出现肝脏脂质积累，并且没有表现出 HADHA 的过度乙酰化。最后，我们发现 GCN5L1 敲除小鼠缺乏在三个特定赖氨酸残基（Lys-350、Lys-383 和 Lys-406）处高度乙酰化的 HADHA，并且这些位点的乙酰化与 HADHA 活性增加显着相关。我们得出结论，GCN5L1 介导的线粒体蛋白乙酰化调节在肝脏代谢稳态中发挥作用。
Sirtuin 3 (SIRT3) deacetylates and activates several mitochondrial fatty acid oxidation enzymes in the liver. Here, we investigated whether the protein acetylase GCN5 general control of amino acid synthesis 5-like 1 (GCN5L1), previously shown to oppose SIRT3 activity, is involved in the regulation of hepatic fatty acid oxidation. We show that GCN5L1 abundance is significantly up-regulated in response to an acute high-fat diet (HFD). Transgenic GCN5L1 overexpression in the mouse liver increased protein acetylation levels, and proteomic detection of specific lysine residues identified numerous sites that are co-regulated by GCN5L1 and SIRT3. We analyzed several fatty acid oxidation proteins identified by the proteomic screen and found that hyperacetylation of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit α (HADHA) correlates with increased GCN5L1 levels. Stable GCN5L1 knockdown in HepG2 cells reduced HADHA acetylation and increased activities of fatty acid oxidation enzymes. Mice with a liver-specific deletion of GCN5L1 were protected from hepatic lipid accumulation following a chronic HFD and did not exhibit hyperacetylation of HADHA compared with WT controls. Finally, we found that GCN5L1-knockout mice lack HADHA that is hyperacetylated at three specific lysine residues (Lys-350, Lys-383, and Lys-406) and that acetylation at these sites is significantly associated with increased HADHA activity. We conclude that GCN5L1-mediated regulation of mitochondrial protein acetylation plays a role in hepatic metabolic homeostasis.