High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT

• Published in: Gut Vol. 73; no. 7; p. 1156
• Main Authors: Bu, Lang, Zhang, Zhengkun, Chen, Jianwen, Fan, Yizeng, Guo, Jinhe, Su, Yaqing, Wang, Huan, Zhang, Xiaomei, Wu, Xueji, Jiang, Qiwei, Gao, Bing, Wang, Lei, Hu, Kunpeng, Zhang, Xiang, Xie, Wei, Wei, Wenyi, Kuang, Ming, Guo, Jianping
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.07.2024
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal models; Animals; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; Cell culture; Cell membranes; Cholesterol; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Hepatocellular carcinoma; High cholesterol diet; High fat diet; Homeostasis; Humans; Kinases; Lipoylation; Liver cancer; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Metabolic disorders; Metabolites; Metastasis; Methionine; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Nutrient deficiency; Nutrition research; Obesity; Palmitic acid; Palmitic Acid - metabolism; Palmitoylation; Phosphatidylinositol 3,4,5-triphosphate; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Regulation; Signal Transduction; Transfection; Tumorigenesis; Tumors; DRUG DEVELOPMENT; MOLECULAR ONCOLOGY; CELL SIGNALLING; HEPATOBILIARY CANCER; FATTY ACID SUPPLEMENTATION
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2023-330826

Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of and knock-in cells, and knockout mice and knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.