Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of precision cut liver slice (PCLS) culture treated with increasing amounts of alpha-linolenic acid and insulin

ABSTRACT: This experiment was designed to test the effect of alpha-linolenic acid (ALA) and insulin on liver slices prepared from Atlantic salmon. Liver slices were incubated with increasing concentrations of ALA and insulin from 20µM to 100µM and 10nM to 100nM, respectively. RNA was subsequently sequenced and response was evaluated and compared to the expected response from Atlantic salmon feeding trials. The purpose of this was to evaluate liver slice culture as a cell culture system for studying lipid metabolism in Atlantic salmon.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Salmo salar

SUBMITTER: Thomas Harvey

PROVIDER: E-MTAB-7366 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Studies in mice have shown that PPARÎ± is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARÎ± in human liver. Here we set out to study the function of PPARÎ± in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARÎ± agonist Wy14643. Results: Quantitative PCR indicated that PPARÎ± is well expressed in human liver and human liver slices and that the classical PPARÎ± targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARÎ± activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARÎ± activation (q value<0.05). Many genes induced by PPARÎ± 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 PPARÎ± activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon Î³-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 PPARÎ± is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARÎ± activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARÎ± were identified that were commonly induced by PPARÎ± activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. Conclusion: Our manuscript demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARÎ± in human liver. Our data underscore the major role of PPARÎ± in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARÎ± in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease. Precision-cut liver slices, prepared from liver biopsies obtained from obese subjects undergoing bariatric surgery, were incubated with the peroxisome proliferator-activated receptor alpha (PPARÎ±) agonist Wy14643 or vehicle for 24hrs, after which gene expression was profiled by array.

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RNA-seq of precision cut liver slice (PCLS) culture treated with increasing amounts of alpha-linolenic acid and insulin

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