ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch.
ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch.
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DOI：
10.1016/j.celrep.2016.09.069
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发表时间：
2016-10-18
期刊：
影响因子：
8.8
通讯作者：
Wellen KE
中科院分区：
文献类型：
--
作者：
Zhao S;Torres A;Henry RA;Trefely S;Wallace M;Lee JV;Carrer A;Sengupta A;Campbell SL;Kuo YM;Frey AJ;Meurs N;Viola JM;Blair IA;Weljie AM;Metallo CM;Snyder NW;Andrews AJ;Wellen KE
代谢灵活性的机制使细胞能够在压力条件下存活，并可能阻碍治疗反应。乙酰辅酶A在能量产生、脂质代谢和表观基因组修饰中起核心作用。在这里，我们表明，在遗传缺失的Acly，基因编码ATP-柠檬酸裂解酶（ACLY），细胞仍然是可行的和增殖，虽然在受损的速度。在不存在ACLY的情况下，细胞上调ACSS 2并利用外源性乙酸盐为从头脂肪生成（DNL）和组蛋白乙酰化提供乙酰辅酶A。生理水平的乙酸盐对于细胞活力和丰富的乙酰辅酶A生产是足够的，尽管组蛋白乙酰化水平在ACLY缺陷细胞中保持低，除非补充高水平的乙酸盐。ACLY缺乏的脂肪细胞在体内积累脂质，表现出从乙酸酯产生的乙酰辅酶A和丙二酰辅酶A增加，并且在脂肪酸含量和合成方面表现出一些差异。总之，这些数据表明，参与乙酸代谢是一个重要的，但部分，补偿ACLY缺乏的机制。Zhao等人证明，ACLY缺乏导致体外增殖细胞和体内脂肪细胞中ACSS 2的上调。乙酸盐是活力所必需的，并且在不存在ACLY的情况下用于脂质合成和组蛋白乙酰化。尽管有ACSS 2补偿，ACLY缺陷细胞的增殖仍受到限制。
Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-CoA plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here we show that upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY), cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL) and histone acetylation. A physiological level of acetate is sufficient for cell viability and abundant acetyl-CoA production, although histone acetylation levels remain low in ACLY-deficient cells unless supplemented with high levels of acetate. ACLY-deficient adipocytes accumulate lipid in vivo, exhibit increased acetyl-CoA and malonyl-CoA production from acetate, and display some differences in fatty acid content and synthesis. Together, these data indicate that engagement of acetate metabolism is a crucial, although partial, mechanism of compensation for ACLY deficiency. Zhao et al. demonstrate that ACLY deficiency causes upregulation of ACSS2 in proliferating cells in vitro and adipocytes in vivo. Acetate is needed for viability and is used for lipid synthesis and histone acetylation in the absence of ACLY. Proliferation is constrained in ACLY-deficient cells despite ACSS2 compensation.