ArticleBMC genomics2015
The impact of PPARα activation on whole genome gene expression in human precision cut liver slices.
Article in BMC genomics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 83 citations in OpenAlex.
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- A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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- In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays.Toxicology and applied pharmacology · 2022Article
- Role of fatty acid transport protein 4 in metabolic tissues: insights into obesity and fatty liver disease.Bioscience reports · 2022Review
- The role of mouse and human peroxisome proliferator-activated receptor-α in modulating the hepatic effects of perfluorooctane sulfonate in mice.Toxicology · 2022Article
- Peroxisome Proliferator-Activated Receptor Activation in Precision-Cut Bovine Liver Slices Reveals Novel Putative PPAR Targets in Periparturient Dairy Cows.Frontiers in veterinary science · 2022Article
- Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor.Frontiers in medicine · 2022Review
- Integrative omics analysis reveals the protective role of vitamin C on perfluorooctanoic acid-induced hepatoxicity.Journal of advanced research · 2022Article
- Polymorphisms analysis for association between ADIPO signaling pathway and genetic susceptibility to T2DM in Chinese han population.Adipocyte · 2021Article
- In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling.Cancers · 2021Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.