Ren Meiling, Xu Huanji, Xia Hongwei, Tang Qiulin, Bi Feng
Department of Abdominal Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
Cell Death Discov. 2021 May 29;7(1):125. doi: 10.1038/s41420-021-00504-1.
Lipid homeostasis plays a fundamental role in the development of hepatocellular carcinoma (HCC). However, the mechanisms that regulate lipid homeostasis to avoid lipotoxicity in HCC remain elusive. Here, we found high-fat diet (HFD) improved the expression of sterol o-acyltransferase1 (SOAT1) and carnitine palmitoyltransferase 1A (CPT1A) in diethylnitrosamine-induced HCC. Bioinformatic analysis showed that SOAT1-mediated fatty acid storage and CPT1A-mediated fatty acids oxidation (FAO) formed a double-negative feedback loop in HCC. We verified that SOAT1 inhibition enhanced CPT1A protein, which shuttled the released fatty acids into the mitochondria for oxidation in vivo and in vitro. Besides, we further confirmed that CPT1A inhibition converted excess fatty acids into lipid drops by SOAT1 in vitro. Simultaneously targeting SOAT1 and CPT1A by the small-molecule inhibitors avasimibe and etomoxir had synergistic anticancer efficacy in HCC in vitro and in vivo. Our study provides new mechanistic insights into the regulation of lipid homeostasis and suggests the combination of avasimibe and etomoxir is a novel strategy for HCC treatment.
脂质稳态在肝细胞癌（HCC）的发展中起着至关重要的作用。然而，在HCC中调节脂质稳态以避免脂毒性的机制仍不清楚。在此，我们发现高脂饮食（HFD）可提高二乙基亚硝胺诱导的HCC中固醇O-酰基转移酶1（SOAT1）和肉碱棕榈酰转移酶1A（CPT1A）的表达。生物信息学分析表明，SOAT1介导的脂肪酸储存和CPT1A介导的脂肪酸氧化（FAO）在HCC中形成了一个双负反馈环。我们证实，抑制SOAT1可增强CPT1A蛋白，后者将释放的脂肪酸转运至线粒体进行体内和体外氧化。此外，我们进一步证实，体外抑制CPT1A可通过SOAT1将过量脂肪酸转化为脂滴。小分子抑制剂阿伐斯汀和依托莫昔同时靶向SOAT1和CPT1A在体外和体内对HCC均具有协同抗癌疗效。我们的研究为脂质稳态调节提供了新的机制见解，并表明阿伐斯汀和依托莫昔联合使用是一种治疗HCC的新策略。
