Oncogene https://doi.org/10.1038/s41388-020-1156-0 ARTICLE Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis Li Gu 1,2 ● Yahui Zhu 1,2 ● Xi Lin 1,2 ● Xingyu Tan 1,2 ● Bingjun Lu 1,2 ● Youjun Li 1,2 Received: 18 April 2019 / Revised: 24 December 2019 / Accepted: 10 January 2020 © The Author(s), under exclusive licence to Springer Nature Limited 2020 Abstract 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/CCl 4 -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. Introduction Fatty acid synthase (FASN) is a critical enzyme for the synthesis of long-chain fatty acids from malonyl-CoA [1] and FASN upregulation has been identified in many cancer types, such as prostate cancer [2], pancreatic cancer [3], breast cancer [4], and colorectal cancer [5]. FASN is highly related with cancer biological aggressiveness and unfavor- able prognosis [6]. FASN overexpression in tumor is dependent on the PI3K–AKT signal transduction pathway and SREBP 1c transcriptional regulation [7, 8]. Moreover, USP2a regulated the stability of FASN in prostate cancer [9], while TIRM21-mediated FASN ubiquitination pro- moted its degradation [10]. Thus, targeting FASN for cancer therapy provides an attractive approach [1]. Glyceronephosphate O-acyltransferase (GNPAT) is a critical rate-limiting enzyme in the biosynthesis of plas- malogens (PIs) and also contributes to the synthesis of fatty acid (FA) [11]. GNPAT knockout mice have been indicated to exhibit substantial defects in eye development, male infertility [12], blood–testis barrier [13], motor defects, and muscle strength with altered neuromuscular junction [14]. Inflammation stimuli reduced GNPAT expression through enhanced c-Myc recruitment onto the GNPAT promoter [15]. GNPAT is also significant for the maturation of semiinvariant natural killer T cells [16]. Recently, we found that GNPAT was amplified and upregulated in HCC patients, and recruited USP30 to stabilize DRP1, leading to promotion of lipid uptake, synthesis, and HCC progression [17]. However, how GNPAT promotes lipogenesis and cancer development remains unclear. Acetyl-CoA Acetyltransferase 1 (ACAT1), a mitochon- drial enzyme, converts two acetyl-CoA molecules to acetoacetyl-CoA and CoA in ketogenesis [18]. It has been reported that ACAT1 and SIRT3 acted as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1 [19]. Moreover, tetrameric ACAT1 was more active and phosphorylated in Y407 through the * Li Gu gulicherry@whu.edu.cn * Youjun Li liy7@whu.edu.cn 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China 2 Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China Supplementary information The online version of this article (https:// doi.org/10.1038/s41388-020-1156-0) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: