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Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice

Author:
Balandaram, Gayathri, Kramer, Lance R., Kang, Boo-Hyon, Murray, Iain A., Perdew, Gary H., Gonzalez, Frank J., Peters, Jeffrey M.
Source:
Toxicology 2016
ISSN:
0300-483X
Subject:
DNA, Hepatitis B virus, Kupffer cells, alanine transaminase, anti-inflammatory activity, apoptosis, blood serum, carcinogenesis, cell proliferation, cyclins, gene expression, hepatitis B, hepatocytes, inflammation, lipopolysaccharides, liver, liver neoplasms, messenger RNA, mice, mutants, risk factors, transgenic animals, tumor necrosis factor-alpha
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.
Agid:
5319623