TNF/TNFR1 promotes palmitic acid-induced insulin resistance in HepG2 cells by suppressing autophagy-associated signaling.

Authors

Yun Zhang, Chen Peng, Mengting Hu, Fei Pan, Mei Liu

Published in

European journal of pharmacology. Pages 179480. Oct 27, 2026. Epub Oct 27, 2026.

Abstract

Intracellular lipid accumulation is intimately associated with palmitic acid (PA)-induced insulin resistance (IR). This study aimed to clarify the role of the tumor necrosis factor (TNF)/tumor necrosis factor receptor 1 (TNFR1) axis in PA-induced IR and lipid metabolic abnormalities in HepG2 cells.
HepG2 cells were exposed to PA (0-500 μM). Cell injury, glucose metabolism, and lipid accumulation were assessed by lactate dehydrogenase (LDH) release, glucose assay, and Oil Red O staining, respectively. Hub genes were identified from the GSE174475 dataset via differential expression and protein-protein interaction analysis. TNFR1 overexpression and TNF silencing were performed to validate function. Autophagic flux was evaluated by LC3 II/p62 expression, immunofluorescence, transmission electron microscopy, and bafilomycin A1 (Baf-A1) treatment.
PA (250 μM) impaired insulin signaling, reducing AKT phosphorylation, plasma membrane glucose transporter 2 (GLUT2)/glucose transporter 4 (GLUT4) levels, glucose uptake, and insulin responsiveness. PA increased TNF expression and promoted lipid accumulation via SREBP1c and lipogenesis/lipid uptake. TNF knockdown attenuated PA-induced IR-related alterations, lipid deposition, and autophagy-related alterations, whereas TNFR1 overexpression reversed these effects. Baf-A1-based flux analysis further suggested that PA impaired autophagic flux, which was restored by TNF knockdown and reversed by TNFR1 overexpression. LC3 II and p62 changes further suggested that TNF/TNFR1 signaling may contribute to this impairment.
TNF may impair autophagic flux and lipid metabolism, thereby contributing to PA-induced lipotoxicity and IR-like phenotypes via TNFR1. These findings provide a rationale for targeting TNF/TNFR1 in the treatment of lipid accumulation-associated IR.

PMID:
42933764
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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