Research Article Details
| Article ID: | A22633 |
| PMID: | 24395441 |
| Source: | J Cell Physiol |
| Title: | Protective effect of the Y220C mutant p53 against steatosis: good news? |
| Abstract: | Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, which may progress to fibrosis, and cirrhosis, leading eventually to hepatocarcinoma development. Recently, cases of hepatocarcinoma have been diagnosed in steatotic patients without nonalcoholic steatohepatitis (NASH) and cirrhosis. The p53 protein, besides its function as tumor suppressor, is emerging as an important regulator of cellular metabolism, but its role in steatosis remains unclear. We induced steatosis in HepG2 (wt-p53) and Huh7.5.1 (Y220C-mutant p53) cells using free fatty acids. We observed a different modulation of p53, different intracellular lipid content, and similar down-regulation of the de novo lipid synthesis genes but opposite modulation of the fatty acid β-oxidation pathway between HepG2 and Huh7.5.1. Accordingly, we found a diverse amount of apoptosis and reactive oxygen species between the two cell lines. Transfection of the wt-p53 in Huh7.5.1 cells reverted the different lipid metabolism behavior observed in these cells. In conclusion, unlike the wt-p53, the Y220C mutant provides a specific protection against steatosis and potentially against its progression. Our findings highlight for the first time an unknown role of a p53 mutant in the setting of steatosis. Being this mutation very frequent in human cancers, this study could be a breakthrough in explaining the occurrence of hepatocarcinoma in steatotic patients without NASH and cirrhosis. |
| DOI: | 10.1002/jcp.24550 |
| 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 |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |