4.7 Article

Combined transcriptome and proteome profiling of the pancreatic β-cell response to palmitate unveils key pathways of β-cell lipotoxicity

期刊

BMC GENOMICS
卷 21, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12864-020-07003-0

关键词

Pancreatic islets; Beta-cells; Free fatty acids; Lipid metabolism; Endoplasmic reticulum stress; RNA-sequencing; Proteome; Type 2 diabetes

资金

  1. European Union's Horizon 2020 research and innovation programme, project T2DSystems [667191]
  2. Innovative Medicines Initiative 2 Joint Undertaking Rhapsody - European Union's Horizon 2020 research and innovation programme [115881]
  3. EFPIA
  4. Swiss State Secretariat for Education, Research and Innovation (SERI) [16.0097]
  5. Fonds National de la Recherche Scientifique (FNRS)
  6. Brussels Region Innoviris project DiaType
  7. Francophone Foundation for Diabetes Research
  8. Fonds Erasme for Medical Research
  9. Novo Nordisk foundation for endocrinological research

向作者/读者索取更多资源

BackgroundProlonged exposure to elevated free fatty acids induces beta -cell failure (lipotoxicity) and contributes to the pathogenesis of type 2 diabetes. In vitro exposure of beta -cells to the saturated free fatty acid palmitate is a valuable model of lipotoxicity, reproducing features of beta -cell failure observed in type 2 diabetes. In order to map the beta -cell response to lipotoxicity, we combined RNA-sequencing of palmitate-treated human islets with iTRAQ proteomics of insulin-secreting INS-1E cells following a time course exposure to palmitate.ResultsCrossing transcriptome and proteome of palmitate-treated beta -cells revealed 85 upregulated and 122 downregulated genes at both transcript and protein level. Pathway analysis identified lipid metabolism, oxidative stress, amino-acid metabolism and cell cycle pathways among the most enriched palmitate-modified pathways. Palmitate induced gene expression changes compatible with increased free fatty acid mitochondrial import and beta -oxidation, decreased lipogenesis and modified cholesterol transport. Palmitate modified genes regulating endoplasmic reticulum (ER) function, ER-to-Golgi transport and ER stress pathways. Furthermore, palmitate modulated cAMP/protein kinase A (PKA) signaling, inhibiting expression of PKA anchoring proteins and downregulating the GLP-1 receptor. SLC7 family amino-acid transporters were upregulated in response to palmitate but this induction did not contribute to beta -cell demise. To unravel critical mediators of lipotoxicity upstream of the palmitate-modified genes, we identified overrepresented transcription factor binding sites and performed network inference analysis. These identified LXR, PPAR alpha, FOXO1 and BACH1 as key transcription factors orchestrating the metabolic and oxidative stress responses to palmitate.ConclusionsThis is the first study to combine transcriptomic and sensitive time course proteomic profiling of palmitate-exposed beta -cells. Our results provide comprehensive insight into gene and protein expression changes, corroborating and expanding beyond previous findings. The identification of critical drivers and pathways of the beta -cell lipotoxic response points to novel therapeutic targets for type 2 diabetes.

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