title: Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice.
abstract: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits steatosis and inflammation, known risk factors for liver cancer. In this study, the effect of ligand activation of PPARβ/δ in modulating liver tumorigenesis in transgenic hepatitis B virus (HBV) mice was examined. Activation of PPARβ/δ in HBV mice reduced steatosis, the average number of liver foci, and tumor multiplicity. Reduced expression of hepatic CYCLIN D1 and c-MYC, tumor necrosis factor alpha (Tnfa) mRNA, serum levels of alanine aminotransaminase, and an increase in apoptotic signaling was also observed following ligand activation of PPARβ/δ in HBV mice compared to controls. Inhibition of Tnfa mRNA expression was not observed in wild-type hepatocytes. Ligand activation of PPARβ/δ inhibited lipopolysaccharide (LPS)-induced mRNA expression of Tnfa in wild-type, but not in Pparβ/δ-null Kupffer cells. Interestingly, LPS-induced expression of Tnfa mRNA was also inhibited in Kupffer cells from a transgenic mouse line that expressed a DNA binding mutant form of PPARβ/δ compared to controls. Combined, these results suggest that ligand activation of PPARβ/δ attenuates hepatic tumorigenesis in HBV transgenic mice by inhibiting steatosis and cell proliferation, enhancing hepatocyte apoptosis, and modulating anti-inflammatory activity in Kupffer cells.
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balandaram
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Lance R
authors.initials: LR
authors.lastname: Kramer
authors.affiliation: Chemon Nonclinical Research Institute, 240 Nampyeong-ro, Yangji-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Boo-Hyon
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA. Electronic address: jmp21@psu.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D006509:Hepatitis B / Q000150:complications*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047494:PPAR delta / Q000187:drug effects* / Q000502:physiology; D048068:PPAR-beta / Q000187:drug effects* / Q000502:physiology; D016133:Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000410:Alanine Transaminase; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: Hepatitis B; Inflammation; Kupffer cell; Liver cancer; Peroxisome proliferator-activated receptor-β/δ