Abstract
BackgroundStudies in mice have shown that PPARα 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 PPARα in human liver. MethodsHere we set out to study the function of PPARα in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARα agonist Wy14643.ResultsQuantitative PCR indicated that PPARα is well expressed in human liver and human liver slices and that the classical PPARα targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARα activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARα activation (q value < 0.05). Many genes induced by PPARα 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 PPARα 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 PPARα is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARα activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARα were identified that were commonly induced by PPARα activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L.ConclusionOur paper demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARα in human liver. Our data underscore the major role of PPARα in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARα in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1969-3) contains supplementary material, which is available to authorized users.
Highlights
Studies in mice have shown that Peroxisome proliferator activated receptor alpha (PPARα) is an important regulator of lipid metabolism in liver and key transcription factor involved in the adaptive response to fasting
To verify that the human liver slices maintain their ability to respond to PPARα activation, we exposed the precision cut liver slices (PCLS) to 100 μM Wy14643, isolated total RNA and performed qPCR to determine the expression of a number of well-established PPARα target genes, including PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 (Fig. 1b)
The main conclusion of our study is that induction of gene expression by PPARα activation is generally well captured and shows significant overlap between human liver slices and primary human hepatocytes, showing consistent upregulation of genes involved in lipid and xenobiotic metabolism in the two model systems
Summary
Studies in mice have shown that PPARα is an important regulator of lipid metabolism in liver and key transcription factor involved in the adaptive response to fasting. PPARs are members of the nuclear receptor superfamily and induce the expression of numerous genes by functioning as ligand-activated transcription factors. Three different PPAR subtypes can be distinguished: PPARα, PPARδ, and PPARγ, each characterized by a distinct tissue expression profile and set of functions [2, 3]. Multiple functions have been assigned to PPARδ, including roles in inflammation, lipid metabolism and cancer [4]. The PPARγ is known as the key transcriptional regulator that drives adipogenesis [5], the process by which fat cells differentiate from pre-adipocytes into mature adipose cells. By serving as the molecular target of the insulin-sensitizing drugs pioglitazone and rosiglitazone, PPARγ is one of the key receptors in the pharmacological treatment of type 2 diabetes [7]
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