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

Xiaoyang Zhu; Qing Liu; Andrew D Patterson; Arun K Sharma; Shantu G Amin; Samuel M Cohen; Frank J Gonzalez; Jeffrey M Peters

doi:10.3390/metabo13080936

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

Metabolites. 2023 Aug 10;13(8):936. doi: 10.3390/metabo13080936.

Authors

Xiaoyang Zhu¹, Qing Liu¹, Andrew D Patterson¹, Arun K Sharma², Shantu G Amin², Samuel M Cohen³, Frank J Gonzalez⁴, Jeffrey M Peters¹

Affiliations

¹ Department of Veterinary and Biomedical Science, The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, State College, PA 16802, USA.
² Department of Pharmacology, The Pennsylvania State University, Hershey, PA 17033, USA.
³ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁴ Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, USA.

Abstract

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.

Keywords: CD4+ T cell; hepatocarcinogenesis; linoleic acid; peroxisome proliferator-activated receptor-α (PPARα); senescence.

Grants and funding

This work was supported in part by the USDA National Institute of Food and Agriculture and Hatch Appropriations under PEN04772.