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.

中文翻译：

---

通过ACAT1介导的GNPAT乙酰化作用稳定FASN可促进脂质代谢和肝癌发生。

适应当地环境的代谢变化已被认为是癌症的标志。GNPAT失调与肝细胞癌（HCC）有关。但是，仍未发现GNPAT的精确翻译后调控。在这里，我们显示ACAT1在额外的棕榈酸（PA）响应中上调。ACAT1在K128处使GNPAT乙酰化，从而抑制TRIM21介导的GNPAT泛素化和降解。相反，SIRT4使GNPAT脱乙酰化会拮抗ACAT1的功能。GNPAT抑制TRIM21介导的FASN降解并促进脂质代谢。此外，shRNA介导的GNPAT的ACAT1消融和乙酰化缺乏抑制异种移植和DEN / CCl4诱导的HCC中的脂质代谢和肿瘤进展。除此以外，ACAT1抑制剂与索拉非尼的组合极大地延缓了小鼠的肿瘤形成。集体，我们证明通过ACAT1介导的GNPAT乙酰化稳定FASN在肝癌发生中起关键作用。