| Summary: | Long-term ligand activation of PPARα in mice causes hepatocarcinogenesis through a mechanism that requires functional PPARα. However, hepatocarcinogenesis is diminished in both <i>Ppara</i>-null and <i>PPARA</i>-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, <i>Ppara</i>-null, and <i>PPARA</i>-humanized mice treated with and without the potent agonist GW7647. The levels of hepatic linoleic acid in <i>Ppara</i>-null and <i>PPARA</i>-humanized mice were markedly higher compared to wild-type controls, along with overall fatty liver. The number of liver CD4<sup>+</sup> T cells was also lower in <i>Ppara</i>-null and <i>PPARA</i>-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 <i>Ppara</i>-null and <i>PPARA</i>-humanized mice with age. These studies suggest a new role for PPARα in age-associated hepatocarcinogenesis due to altered lipid metabolism in <i>Ppara</i>-null and <i>PPARA</i>-humanized mice and the accumulation of linoleic acid as part of an overall fatty liver that is associated with loss of CD4<sup>+</sup> T cells in the liver in both transgenic models. Since fatty liver is a known causal risk factor for liver cancer, <i>Ppara</i>-null and <i>PPARA</i>-humanized mice are valuable models for examining the mechanisms of PPARα and age-dependent hepatocarcinogenesis.
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