Accumulation of Linoleic Acid by Altered Peroxisome Proliferator-Activated Receptor-a Signaling Is Associated with Age-Dependent Hepatocarcinogenesis in Ppara Transgenic Mice

Long-term ligand activation of PPARa in mice causes hepatocarcinogenesis through a mechanism that requires functional PPARa. 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 PPARa agonist. Since PPARa 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 TNFa and IFN? levels were observed in Ppara-null and PPARA-humanized mice with age. These studies suggest a new role for PPARa 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 PPARa and age-dependent hepatocarcinogenesis.