Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis
Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis
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ACAT1 介导的 GNPAT 乙酰化稳定 FASN 促进脂质代谢和肝癌发生
DOI：
10.1038/s41388-020-1156-0
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发表时间：
2020-01-23
期刊：
影响因子：
8
通讯作者：
Li, Youjun
中科院分区：
文献类型：
--
作者：
Gu, Li;Zhu, Yahui;Li, Youjun
适应局部环境的代谢改变已被认为是癌症的标志。GNPAT失调与肝细胞癌（HCC）有关。然而，GNPAT的精确的翻译后调节仍然未被发现。在这里，我们表明，ACAT 1是上调响应额外的棕榈酸（PA）。ACAT 1在K128处乙酰化GNPAT，其抑制TRIM 21介导的GNPAT泛素化和降解。相反，SIRT 4对GNPAT的脱乙酰化作用会拮抗ACAT 1的功能。GNPAT抑制TRIM 21介导的FAT 1降解并促进脂质代谢。此外，在异种移植和DEN/CCl 4诱导的HCC中，shRNA介导的ACAT 1消融和GNPAT的乙酰化缺陷抑制脂质代谢和肿瘤进展。另外，ACAT 1抑制剂与索拉非尼的组合极大地延缓了小鼠中的肿瘤形成。总的来说，我们证明了ACAT 1介导的GNPAT乙酰化对FASN的稳定在肝癌发生中发挥着关键作用。
Metabolic alteration for adaptation of the local environment has been recognized as a hallmark of cancer. GNPAT dysregulation has been implicated in hepatocellular carcinoma (HCC). However, the precise posttranslational regulation of GNPAT is still undiscovered. Here we show that ACAT1 is upregulated in response to extra palmitic acid (PA). ACAT1 acetylates GNPAT at K128, which represses TRIM21-mediated GNPAT ubiquitination and degradation. Conversely, GNPAT deacetylation by SIRT4 antagonizes ACAT1's function. GNPAT represses TRIM21-mediated FASN degradation and promotes lipid metabolism. Furthermore, shRNA-mediated ACAT1 ablation and acetylation deficiency of GNPAT repress lipid metabolism and tumor progression in xenograft and DEN/CCl4-induced HCC. Otherwise, ACAT1 inhibitor combination with sorafenib enormously retards tumor formation in mice. Collectively, we demonstrate that stabilization of FASN by ACAT1-mediated GNPAT acetylation plays a critical role in hepatocarcinogenesis.