Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease.

Abstract

Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid β-oxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1α, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose up-regulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1-knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the α subunit of the stimulatory G protein (Gsα), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC-1α and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial β-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.

• Authors: Maja Dembic, Henriette S Andersen, Jean Bastin, Thomas K Doktor, Thomas J Corydon, Jörn Oliver Sass, Alexandra Lopes Costa, Fatima Djouadi, Brage S Andresen
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 126 Issue 1 Pg. 64-76 (01 2019) ISSN: 1096-7206 [Electronic] United States
• PMID: 30446350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Myelin Basic Protein
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Receptors, G-Protein-Coupled
• SLC52A1 protein, human
• Transcription Factors
• Amidohydrolases
• SIRT1 protein, human
• Sirtuin 1
• aspartoacylase
• Glucose
• Resveratrol

Topics

• Amidohydrolases (genetics)
• Canavan Disease (diagnosis, drug therapy)
• Cell Line
• Cells, Cultured
• Fibroblasts (drug effects)
• Gene Expression Regulation
• Genes, p53
• Glucose (metabolism)
• High-Throughput Nucleotide Sequencing
• Humans
• Lipid Metabolism
• Molecular Targeted Therapy
• Myelin Basic Protein (genetics)
• Oxidation-Reduction
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics)
• Receptors, G-Protein-Coupled (genetics)
• Resveratrol (pharmacology)
• Sequence Analysis, RNA
• Sirtuin 1 (genetics)
• Transcription Factors (genetics)
• Up-Regulation