The whole genome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice

Dataset

Description

The role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the effect of PPARα activation in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver by combining transcriptomics with the use of hepatocyte humanized livers. To that end, chimeric mice containing hepatocyte humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days. Livers were collected and analysed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on fenofibrate treatment in normal mice. The human hepatocytes exhibited excessive lipid accumulation. Fenofibrate increased the size of the mouse but not human hepatocytes, and tended to reduce steatosis in the human hepatocytes. Quantitative PCR indicated that induction of PPARα targets by fenofibrate was less pronounced in the human hepatocytes than in the residual mouse hepatocytes. Transcriptomics analysis indicated that, after filtering, a total of 282 genes was significantly different between fenofibrate- and control-treated mice (P<0.01). 123 genes were significantly lower and 159 genes significantly higher in the fenofibrate-treated mice, including many established PPARα targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2. According to gene set enrichment analysis, fenofibrate upregulated interferon/cytokine signaling-related pathways in hepatocyte humanized liver, but downregulated these pathways in normal mouse liver. Also, fenofibrate downregulated pathways related to DNA synthesis in hepatocyte humanized liver but not in normal mouse liver. The results support the major role of PPARα in regulating hepatic lipid metabolism, and underscore the more modest effect of PPARα activation on gene regulation in human liver compared to mouse liver. The data suggest that PPARα may have a suppressive effect on DNA synthesis in human liver, and a stimulatory effect on interferon/cytokine signalling.
Date made available28 May 2018
PublisherWageningen University

Research Output

The whole transcriptome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice

de la Rosa Rodriguez, M. A., Sugahara, G., Hooiveld, G. J. E. J., Ishida, Y., Tateno, C. & Kersten, S., 7 Jun 2018, In : BMC Genomics. 19, 443.

Research output: Contribution to journalArticleAcademicpeer-review

Open Access
  • 4 Citations (Scopus)

    Cite this

    de la Rosa Rodriguez, M. A. (Creator), Sugahara, G. (Creator), Ishida, Y. (Creator), Tateno, C. (Creator), Kersten, A. H. (Creator) (28 May 2018). The whole genome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice. Wageningen University.