Research Article Details
| Article ID: | A10254 |
| PMID: | 31409773 |
| Source: | Cell Death Dis |
| Title: | mTOR direct crosstalk with STAT5 promotes de novo lipid synthesis and induces hepatocellular carcinoma. |
| Abstract: | Hepatocellular carcinoma (HCC) can be the last step of nonalcoholic fatty liver disease (NAFLD) evolution, and the main characteristic of NAFLD is alteration in lipid metabolism. However, the mechanisms of abnormal lipid metabolism in NAFLD and HCC progression are yet to be identified. Here, we demonstrate that liver-specific activation of mTORC1 promoted the expression of lipid synthesis genes and lead to the development of spontaneous HCC. Genetic mouse models developed spontaneous HCC along with increased expressions of SREBP1, ACC1 and FASN. In addition, high levels of p-STAT5 were observed in the livers and particularly evident in the tumor area. And the synthesis of p-STAT5 was increased in patients along with the increase in SREBP1 synthesis in clinical samples. Moreover, mTORC1 interacts with and phosphorylates the STAT5 in hepatocytes. In conclusion, our data suggested that mTORC1 upregulates SREBP1 transcription via crosstalk with the STAT5 pathway which contributes to the NAFLD-related HCC pathogenesis. And the inhibitor of SREBP1 and mTOR may help to prevent HCC in clinical NAFLD patients. |
| DOI: | 10.1038/s41419-019-1828-2 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D612 | Rapamycin | Miscellany | -- | Immunosuppressants; Methylmalonyl CoA mutase stimulants; MTOR protein inhibitors; T lymphocyte inhibitors | -- | Under investigation | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |