Peroxisome proliferator-activated receptor α (PPARα) is closely related to lipid metabolism and various liver diseases. Previous study has shown that chronic treatment with PPARα agonist WY-14643 can induce liver tumors in rodents, but the implications of this process on lipid metabolism in the liver remain unclear. Thus, this study aimed to explore the influences of chronic treatment with WY-14643 on the liver and hepatic lipid metabolism. Wild-type C57BL/6 mice were treated with WY-14643 (100 mg/kg/week, i.p.) or corn oil, and liver and serum samples were collected for testing after 42 weeks of WY-14643 treatment. The results showed that hepatomegaly, liver tumors with mild liver injury, and hepatocyte proliferation were induced in mice treated with WY-14643. The mRNA and protein expression levels of PPARα downstream targets acyl-CoA oxidase 1 and cytochrome P450 4A were significantly upregulated in the WY-14643–treated group. Lipidomic analysis revealed that chronic treatment with WY-14643 disturbed lipid homeostasis, especially triglycerides (TGs), which were significantly elevated after WY-14643 treatment. Moreover, TG homeostasis-related genes were significantly increased in the WY-14643–treated group. In conclusion, these findings demonstrated that hepatomegaly and liver tumors induced by chronic treatment with WY-14643 in mice are accompanied by hepatocyte proliferation and TG accumulation.

SIGNIFICANCE STATEMENT The present study clearly demonstrated that sustained peroxisome proliferator-activated receptor α (PPARα) activation by chronic treatment with WY-14643 induces hepatomegaly and liver tumors with triglyceride accumulation by regulating lipid homeostasis-related genes in mice. These findings may help to clarify the influences of sustained PPARα activation on liver lipid homeostasis and provide data for the clinically rational use of drugs that can activate PPARα.

The work was supported by the Natural Science Foundation of China [Grant 82025034, 81973392, 82000593, 82274001, 82204226]; the Shenzhen Science and Technology Program [KQTD20190929174023858]; the National Key Research and Development Program [Grant 2017YFE0109900]; the 111 project [Grant B16047]; the Key Laboratory Foundation of Guangdong Province [Grant 2017B030314030]; the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [Grant 2017BT01Y093]; the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province) [Grant 2017B090903004].

The authors declare that they have no actual or perceived conflicts of interest with the contents of this article.

↵1 J.Y. and S.F. contributed equally to this work.

dx.doi.org/10.1124/dmd.120.000908.

↵This article has supplemental material available at dmd.aspetjournals.org.