Fei Mintian, Zhang Yi, Li Haolin, Xu Qili, Gao Yu, Yang Cheng, Li Weiyi, Liang Chaozhao, Wang Baojun, Xiao Haibing
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China.
Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China.
Int J Biol Sci. 2025 Jan 1;21(2):614-631. doi: 10.7150/ijbs.103032. eCollection 2025.
The current research revealed a strong link between lipid reprogramming and dysregulated lipid metabolism to the genesis and development of clear cell renal cell carcinoma (ccRCC). Pathologically, ccRCC exhibits a high concentration of lipid droplets within the cytoplasm. HIF-2α expression has previously been demonstrated to be elevated in ccRCC caused by mutations in the von Hippel-Lindau (VHL) gene, which plays a vital role in the development of renal cell carcinoma. Nevertheless, the mechanisms by which HIF-2α influences lipid metabolism reprogramming are unknown. Our investigation demonstrated that HIF-2α directly binds to the promoter region of LPCAT1, promoting its transcription. RNA-seq and lipidomics mass spectrometry studies showed that knocking down LPCAT1 significantly reduced triglyceride production. Research suggests that KD-LPCAT1 involves activation of the NF-κB signaling pathway, which activates F-Box/WD Repeat-Containing Protein 7 (FBXW7). FBXW7, an E3 ubiquitin ligase involved in lipid metabolism, interacts with ATP Citrate Lyase (ACLY) to promote its degradation, lowering fatty acid production and contributing to the lipid content reduction.
目前的研究揭示了脂质重编程和脂质代谢失调与透明细胞肾细胞癌（ccRCC）的发生发展之间存在紧密联系。在病理上，ccRCC在细胞质内表现出高浓度的脂滴。先前已证明，在由冯·希佩尔-林道（VHL）基因突变引起的ccRCC中，缺氧诱导因子-2α（HIF-2α）表达升高，而VHL基因在肾细胞癌的发展中起着至关重要的作用。然而，HIF-2α影响脂质代谢重编程的机制尚不清楚。我们的研究表明，HIF-2α直接结合溶血磷脂酰胆碱酰基转移酶1（LPCAT1）的启动子区域，促进其转录。RNA测序和脂质组学质谱研究表明，敲低LPCAT1可显著降低甘油三酯的产生。研究表明，敲低LPCAT1涉及核因子κB（NF-κB）信号通路的激活，该通路激活含F-Box/ WD重复序列蛋白7（FBXW7）。FBXW7是一种参与脂质代谢的E3泛素连接酶，它与ATP柠檬酸裂解酶（ACLY）相互作用以促进其降解，降低脂肪酸生成并导致脂质含量减少。
