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: Gayathri Balandaram, Lance R Kramer, Boo-Hyon Kang, Iain A Murray, Gary H Perdew, Frank J Gonzalez, Jeffrey M Peters
• Journal: Toxicology (Toxicology) Vol. 363-364 Pg. 1-9 (07 01 2016) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 27427494 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Ligands
• PPAR delta
• PPAR-beta
• Thiazoles
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• Alanine Transaminase

Topics

• Alanine Transaminase (blood)
• Animals
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects, metabolism)
• Hepatitis B (complications)
• Hepatocytes (metabolism, pathology)
• Kupffer Cells (metabolism, pathology)
• Ligands
• Liver Neoplasms (metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• PPAR delta (drug effects, physiology)
• PPAR-beta (drug effects, physiology)
• Polymerase Chain Reaction
• Thiazoles (pharmacology)