TY - JOUR
T1 - Diminished Hepatocarcinogenesis by a Potent, High-Affinity Human PPARα Agonist in PPARA-Humanized Mice
AU - Foreman, Jennifer E.
AU - Koga, Takayuki
AU - Kosyk, Oksana
AU - Kang, Boo Hyon
AU - Zhu, Xiaoyang
AU - Cohen, Samuel M.
AU - Billy, Laura J.
AU - Sharma, Arun K.
AU - Amin, Shantu
AU - Gonzalez, Frank J.
AU - Rusyn, Ivan
AU - Peters, Jeffrey M.
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For permissions, please e-mail: [email protected].
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Ppara-null and PPARA-humanized mice are refractory to hepatocarcinogenesis caused by the peroxisome proliferator-Activated receptor-α (PPARα) agonist Wy-14,643. However, the duration of these earlier studies was limited to approximately 1 year of treatment, and the ligand used has a higher affinity for the mouse PPARα compared to the human PPARα. Thus, the present study examined the effect of long-Term administration of a potent, high-Affinity human PPARα agonist (GW7647) on hepatocarcinogenesis in wild-Type, Ppara-null, or PPARA-humanized mice. In wild-Type mice, GW7647 caused hepatic expression of known PPARα target genes, hepatomegaly, hepatic MYC expression, hepatic cytotoxicity, and a high incidence of hepatocarcinogenesis. By contrast, these effects were essentially absent in Ppara-null mice or diminished in PPARA-humanized mice, although hepatocarcinogenesis was observed in both genotypes. Enhanced fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647. PPARA-humanized mice administered GW7647 also exhibited increased necrosis after 5 weeks of treatment. Results from these studies demonstrate that the mouse PPARα is required for hepatocarcinogenesis induced by GW7647 administered throughout adulthood. Results also indicate that a species difference exists between rodents and human PPARα in the response to ligand activation of PPARα. The hepatocarcinogenesis observed in control and treated Ppara-null mice is likely mediated in part by increased hepatic fatty change, whereas the hepatocarcinogenesis observed in PPARA-humanized mice may also be due to enhanced fatty change and cytotoxicity that could be influenced by the minimal activity of the human PPARα in this mouse line on downstream mouse PPARα target genes. The Ppara-null and PPARA-humanized mouse models are valuable tools for examining the mechanisms of PPARα-induced hepatocarcinogenesis, but the background level of liver cancer must be controlled for in the design and interpretation of studies that use these mice.
AB - Ppara-null and PPARA-humanized mice are refractory to hepatocarcinogenesis caused by the peroxisome proliferator-Activated receptor-α (PPARα) agonist Wy-14,643. However, the duration of these earlier studies was limited to approximately 1 year of treatment, and the ligand used has a higher affinity for the mouse PPARα compared to the human PPARα. Thus, the present study examined the effect of long-Term administration of a potent, high-Affinity human PPARα agonist (GW7647) on hepatocarcinogenesis in wild-Type, Ppara-null, or PPARA-humanized mice. In wild-Type mice, GW7647 caused hepatic expression of known PPARα target genes, hepatomegaly, hepatic MYC expression, hepatic cytotoxicity, and a high incidence of hepatocarcinogenesis. By contrast, these effects were essentially absent in Ppara-null mice or diminished in PPARA-humanized mice, although hepatocarcinogenesis was observed in both genotypes. Enhanced fatty change (steatosis) was also observed in both Ppara-null and PPARA-humanized mice independent of GW7647. PPARA-humanized mice administered GW7647 also exhibited increased necrosis after 5 weeks of treatment. Results from these studies demonstrate that the mouse PPARα is required for hepatocarcinogenesis induced by GW7647 administered throughout adulthood. Results also indicate that a species difference exists between rodents and human PPARα in the response to ligand activation of PPARα. The hepatocarcinogenesis observed in control and treated Ppara-null mice is likely mediated in part by increased hepatic fatty change, whereas the hepatocarcinogenesis observed in PPARA-humanized mice may also be due to enhanced fatty change and cytotoxicity that could be influenced by the minimal activity of the human PPARα in this mouse line on downstream mouse PPARα target genes. The Ppara-null and PPARA-humanized mouse models are valuable tools for examining the mechanisms of PPARα-induced hepatocarcinogenesis, but the background level of liver cancer must be controlled for in the design and interpretation of studies that use these mice.
KW - hepatocarcinogenesis
KW - peroxisome proliferator-Activated receptors (PPARs)
KW - species difference
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U2 - 10.1093/toxsci/kfab067
DO - 10.1093/toxsci/kfab067
M3 - Article
C2 - 34081128
AN - SCOPUS:85115018329
SN - 1096-6080
VL - 183
SP - 70
EP - 80
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -