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

被引:32
作者
Bu, Lang [1 ,2 ]
Zhang, Zhengkun [2 ]
Chen, Jianwen [2 ]
Fan, Yizeng [3 ]
Guo, Jinhe [2 ]
Su, Yaqing [2 ]
Wang, Huan [2 ]
Zhang, Xiaomei [2 ]
Wu, Xueji [2 ]
Jiang, Qiwei [2 ]
Gao, Bing [2 ]
Wang, Lei [2 ]
Hu, Kunpeng [4 ]
Zhang, Xiang [5 ,6 ]
Xie, Wei [2 ]
Wei, Wenyi [3 ]
Kuang, Ming [1 ]
Guo, Jianping [2 ]
机构
[1] Sun Yat Sen Univ, Affiliated Hosp 1, Ctr Hepatopancreate Biliary Surg, Guangzhou, Guangdong, Peoples R China
[2] Sun Yat Sen Univ, Affiliated Hosp 1, Inst Precis Med, Guangzhou, Guangdong, Peoples R China
[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA
[4] Sun Yat Sen Univ, Affiliated Hosp 3, Div Gen Surg, Guangzhou, Guangdong, Peoples R China
[5] Chinese Univ Hong Kong, Inst Digest Dis, Li Ka Shing Inst Hlth Sci, State Key Lab Digest Dis, Hong Kong, Peoples R China
[6] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Dept Med & Therapeut, Hong Kong, Peoples R China
关键词
CELL SIGNALLING; DRUG DEVELOPMENT; FATTY ACID SUPPLEMENTATION; HEPATOBILIARY CANCER; MOLECULAR ONCOLOGY; ACID SYNTHASE; KINASE; HOMEOSTASIS; GROWTH;
D O I
10.1136/gutjnl-2023-330826
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
ObjectiveWhether 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.DesignMetabolite 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 AKT1C77S and AKT1C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1C224S 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.ResultsBy 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.ConclusionsOur 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.
引用
收藏
页码:1156 / 1168
页数:13
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