The impact of PPARaα activation on whole genome gene expression in human precision cut liver slices

Abstract

Background: Studies in mice have shown that PPARaα is an important regulator of lipid metabolism in liver and key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARaα in human liver. Methods: Here we set out to study the function of PPARaα in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARaα agonist Wy14643. Results: Quantitative PCR indicated that PPARaα is well expressed in human liver and human liver slices and that the classical PPARaα targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARaα activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARaα activation (q value < 0.05). Many genes induced by PPARaα activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARaα activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon γ-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARaα is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARaα activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARaα were identified that were commonly induced by PPARaα activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. Conclusion: Our paper demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARaα in human liver. Our data underscore the major role of PPARaα in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARaα in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease.