Abstract
BackgroundThe role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the role of PPARα in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver. 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 analyzed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on PPARα activation in normal mouse liver, human primary hepatocytes, and human precision cut liver slices.ResultsOf the different human liver models, the gene expression profile of hepatocyte humanized livers most closely resembled actual human liver. In the hepatocyte humanized mouse livers, 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.ConclusionThe 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.
Highlights
The role of PPARα in gene regulation in mouse liver is well characterized
The results clearly indicate that the gene expression profiles of hepatocyte humanized liver samples are much closer to human liver as compared to human primary hepatocytes and human liver slices
We found that PPARα activation in chimeric mice with hepatocyte humanized livers causes the downregulation of genes and pathways connected to DNA synthesis, further strengthening the notion that the effects of PPARα activation on DNA synthesis, cell proliferation and hepato-carcinogenesis are distinct between mouse liver and human liver
Summary
The role of PPARα in gene regulation in mouse liver is well characterized. less is known about the role of PPARα in human liver. The Peroxisome Proliferator Activated Receptors (PPARs) are a group of nuclear receptors involved in the transcriptional regulation of a variety of biological processes, including lipid metabolism and inflammation [1,2,3]. Fasted PPARα−/− mice suffer from a host of metabolic abnormalities including hypoglycemia, hypoketonemia, elevated plasma non-esterified fatty acids, and a fatty liver. These metabolic defects are rooted in defective transcription of hundreds of genes involved in numerous metabolic pathways covering nearly every aspect of hepatic lipid metabolism [13]. Besides its role as key transcriptional regulator of lipid metabolism during fasting, PPARα is mainly known as the receptor for a diverse group of compounds known as peroxisome proliferators [14, 15]. Studies using human liver model systems have largely allayed these concerns by failing to find supportive evidence for a proliferative and pro-carcinogenic effect of PPARα ligands in human cells [19]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
