| Autor: |
Xiaoyang Zhu, Qing Liu, Andrew D. Patterson, Arun K. Sharma, Shantu G. Amin, Samuel M. Cohen, Frank J. Gonzalez, Jeffrey M. Peters |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Metabolites, Vol 13, Iss 8, p 936 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2218-1989 |
| DOI: |
10.3390/metabo13080936 |
| Popis: |
Long-term ligand activation of PPARα in mice causes hepatocarcinogenesis through a mechanism that requires functional PPARα. However, hepatocarcinogenesis is diminished in both Ppara-null and PPARA-humanized mice, yet both lines develop age-related liver cancer independently of treatment with a PPARα agonist. Since PPARα is a master regulator of liver lipid metabolism in the liver, lipidomic analyses were carried out in wild-type, Ppara-null, and PPARA-humanized mice treated with and without the potent agonist GW7647. The levels of hepatic linoleic acid in Ppara-null and PPARA-humanized mice were markedly higher compared to wild-type controls, along with overall fatty liver. The number of liver CD4+ T cells was also lower in Ppara-null and PPARA-humanized mice and was negatively correlated with the elevated linoleic acid. Moreover, more senescent hepatocytes and lower serum TNFα and IFNγ levels were observed in Ppara-null and PPARA-humanized mice with age. These studies suggest a new role for PPARα in age-associated hepatocarcinogenesis due to altered lipid metabolism in Ppara-null and PPARA-humanized mice and the accumulation of linoleic acid as part of an overall fatty liver that is associated with loss of CD4+ T cells in the liver in both transgenic models. Since fatty liver is a known causal risk factor for liver cancer, Ppara-null and PPARA-humanized mice are valuable models for examining the mechanisms of PPARα and age-dependent hepatocarcinogenesis. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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