Back to Search
Start Over
Active AKT2 stimulation of SREBP1/SCD1-mediated lipid metabolism boosts hepatosteatosis and cancer.
- Source :
-
Translational research : the journal of laboratory and clinical medicine [Transl Res] 2024 Jun; Vol. 268, pp. 51-62. Date of Electronic Publication: 2024 Jan 18. - Publication Year :
- 2024
-
Abstract
- 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 Akt2 <superscript>E17K</superscript> 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.<br /> (Copyright © 2024. Published by Elsevier Inc.)
- Subjects :
- Animals
Humans
Male
Mice
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Carcinoma, Hepatocellular genetics
Diet, High-Fat adverse effects
Fatty Liver metabolism
Fatty Liver pathology
Mice, Inbred C57BL
Lipid Metabolism
Liver Neoplasms metabolism
Liver Neoplasms pathology
Proto-Oncogene Proteins c-akt metabolism
Stearoyl-CoA Desaturase metabolism
Stearoyl-CoA Desaturase genetics
Sterol Regulatory Element Binding Protein 1 metabolism
Sterol Regulatory Element Binding Protein 1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1810
- Volume :
- 268
- Database :
- MEDLINE
- Journal :
- Translational research : the journal of laboratory and clinical medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38244769
- Full Text :
- https://doi.org/10.1016/j.trsl.2024.01.005