Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2

作者：Siying Wang, Yangyang Zhou, Ruobing Yu, Ling Jing, Botai Li, Yang Chen, Zhuoan Cheng, Ruolan Qian, Zhang Lin, Chengtao Yu, Jiaojiao Zheng, Xingling Zheng, Qi Jia, Wei Wu, Qiangxin Wu, Mengnuo Chen, Shengxian Yuan, Wei Dong, Yao Shi, Robin Jansen, Yang Chen, Yujun Hao, Ming Yao, Wenxin Qin, Haojie Jin · 发表于：JHEP Reports · 年份：2023 · DOI：10.1016/j.jhepr.2023.100843 · 被引用次数：30 · 研究领域：Peroxisome Proliferator-Activated Receptors、Inflammatory mediators and NSAID effects、Cancer, Lipids, and Metabolism

Background & Aims Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout ( Ftcd- LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spo...