Chronic Treatment With WY-14643 Induces Tumorigenesis and Triglyceride Accumulation in Mouse Livers

作者：Yang, Jie; Fan, Shicheng; Zhang, Yifei; Huang, Min^*; Gao, Yue^*; Bi, Huichang^*

来源：Drug Metabolism and Disposition, 2022, 50(12): 1464-1471.

DOI：10.1124/dmd.122.000908

• ACTIVATED-RECEPTOR-ALPHA
• PPAR-ALPHA
• LIPID-METABOLISM
• ADAPTIVE RESPONSE
• NUCLEAR RECEPTORS
• OXIDATIVE STRESS
• PEROXISOME
• INDUCTION
• MICE
• PROLIFERATION

Peroxisome proliferator-activated receptor a (PPARa) is closely re-lated to lipid metabolism and various liver diseases. Previous study has shown that chronic treatment with PPARa 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 af-ter 42 weeks of WY-14643 treatment. The results showed that hepa-tomegaly, liver tumors with mild liver injury, and hepatocyte proliferation were induced in mice treated with WY-14643. The mRNA and protein expression levels of PPARa downstream tar-gets acyl-CoA oxidase 1 and cytochrome P450 4A were signifi-cantly upregulated in the WY-14643-treated group. Lipidomic analysis revealed that chronic treatment with WY-14643 disturbed lipid homeostasis, especially triglycerides (TGs), which were sig-nificantly elevated after WY-14643 treatment. Moreover, TG homeo-stasis-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 prolifera-tion and TG accumulation.SIGNIFICANCE STATEMENTThe present study clearly demonstrated that sustained peroxisome proliferator-activated receptor a (PPARa) activation by chronic treat-ment with WY-14643 induces hepatomegaly and liver tumors with tri-glyceride accumulation by regulating lipid homeostasis-related genes in mice. These findings may help to clarify the influences of sustained PPARa activation on liver lipid homeostasis and provide data for the clinically rational use of drugs that can activate PPARa.

• 单位
  南方医科大学; 中山大学; y