Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer

Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet po...

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Published in:Translational research : the journal of laboratory and clinical medicine 2024-06, Vol.268, p.51-62
Main Authors: Huang, Fuqiang, Zhao, Na, Cai, Pei, Hou, Mengjie, Yang, Shuhui, Zheng, Bohao, Ma, Qian, Jiang, Jingpeng, Gai, Xiaochen, Mao, Yilei, Wang, Lianmei, Hu, Zhongdong, Zha, Xiaojun, Liu, Fangming, Zhang, Hongbing
Format: Article
Language:English
Subjects:
AKT2
Animals
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Diet, High-Fat - adverse effects
Fatty Liver - metabolism
Fatty Liver - pathology
Hepatocellular carcinoma
Hepatosteatosis
Humans
Inflammation
Lipid Metabolism
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Mice
Mice, Inbred C57BL
Monounsaturated fatty acid
Proto-Oncogene Proteins c-akt - metabolism
Stearoyl-CoA Desaturase - genetics
Stearoyl-CoA Desaturase - metabolism
Sterol Regulatory Element Binding Protein 1 - genetics
Sterol Regulatory Element Binding Protein 1 - metabolism
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Summary:Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet potentiated mouse liver AKT2. Hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice. AKT2 activation also exacerbated lipopolysaccharide and D-galactosamine hydrochloride-induced injury/inflammation and N-Nitrosodiethylamine (DEN)-induced HCC. A positive correlation between AKT2 activity and SCD1 expression was observed in human HCC samples. Activated AKT2 enhanced the production of monounsaturated fatty acid which was dependent on SREBP1 upregulation of SCD1. Blockage of active SREBP1 and ablation of SCD1 reduced steatosis, inflammation, and tumor burden in DEN-treated Akt2E17K mice. Therefore, AKT2 activation is crucial for the development of steatosis-associated HCC which can be treated with blockage of AKT2-SREBP1-SCD1 signaling cascade.
ISSN:1931-5244
1878-1810
DOI:10.1016/j.trsl.2024.01.005