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Palmitate drives mitochondrial and ER stress through disruption of the CD73-Adenosine axis

ABSTRACT: Bulk RNA sequencing was used to characterize transcriptional changes associated with the dysfunctional metabolic state in murine gingival fibroblasts (mGF). The mGF were treated with BSA control, palmitate, IL-1β, or palmitate plus IL-1β. Gene ontology analysis demonstrated enrichment of pathways related to innate immune activation, oxidative stress, mitochondrial dysfunction, ER stress, and purine metabolism. Palmitate disrupts the Cd73-adenosine axis while promoting mitochondrial dysfunction, oxidative stress, and Perk-mediated ER stress in gingival fibroblasts. Adenosine signaling protects against lipotoxic-induced ER stress, highlighting the relevance of the Cd73-adenosine pathway for metabolic and inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE334095 | GEO | 2026/07/08

REPOSITORIES: GEO

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Project description:Background: Prolonged exposure to elevated free fatty acids induces β-cell failure (lipotoxicity) and contributes to the pathogenesis of type 2 diabetes. In vitro exposure of β-cells to the saturated free fatty acid palmitate is a valuable model of lipotoxicity, reproducing features of β-cell failure observed in type 2 diabetes. In order to map the β-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. Results: Crossing transcriptome and proteome of palmitate-treated β-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 β-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 β-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, PPARα, FOXO1 and BACH1 as key transcription factors orchestrating the metabolic and oxidative stress responses to palmitate. Conclusions: This is the first study to combine transcriptomic and sensitive time course proteomic profiling of palmitate-exposed β-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 β-cell lipotoxic response points to novel therapeutic targets for type 2 diabetes.

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Palmitate drives mitochondrial and ER stress through disruption of the CD73-Adenosine axis

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