ArticleEuropean journal of medical research2025
Overexpression of the lncRNA TUG1 regulates high-glucose-induced endocytic clearance dysfunction in HLSECs via the Wnt/β-catenin signaling pathway.
Article in European journal of medical research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundType 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are linked to endocytic clearance dysfunction in liver sinusoidal endothelial cells (LSECs), which accelerates their synergistic progression. Long noncoding RNA TUG1 (lncRNA TUG1) bridges these two diseases, but its mechanism in alleviating high glucose-induced endocytic impairment in human LSECs (HLSECs) remains unclear.
methodsHLSECs were cultured under standard conditions. A lentiviral lncRNA TUG1 overexpression vector (LV-lncRNA TUG1) was generated via genetic recombination and transduced into HLSECs. Six experimental groups were established: negative control (NC), high glucose (HG), HG + LV-lncRNA TUG1, HG + empty vector control (LV-CON), HG + LV-lncRNA TUG1 + XAV939, HG + LV-CON + XAV939. Quantitative real-time polymerase chain reaction (qRT-PCR) detected lncRNA TUG1 expression levels. β-Catenin and other relevant molecules were assayed by qRT-PCR and Western blot. Immunofluorescence staining detected β-catenin localization to assess Wnt/β-catenin pathway activation. Dil-labeled low-density lipoprotein (Dil-LDL) and fluorescence microscopy evaluated cellular LDL uptake. We further explored TUG1's regulatory effects on downstream molecules and mechanisms under high glucose.
resultsHigh glucose downregulates lncRNA TUG1 expression in HLSECs, which in turn induces endocytic clearance dysfunction-characterized by elevated CAV-1 expression, reduced PLVAP levels, and impaired DiI-LDL endocytic activity-and concurrently activates the Wnt/β-catenin pathway (enhanced β-catenin phosphorylation and nuclear translocation, as well as upregulated Cyclin D1 expression). TUG1 overexpression significantly attenuates these pathological changes, while the Wnt/β-catenin pathway inhibitor XAV939 further potentiates TUG1's protective effect. DISCUSSION: This study identifies a novel mechanism by which high glucose-induced TUG1 downregulation activates the Wnt/β-catenin pathway, contributing to HLSEC endocytic impairment. TUG1 overexpression mitigates these pathological processes, with XAV939 enhancing its protective role, providing new insights into MAFLD's mechanistic basis. However, the study is limited to in vitro experiments, requiring in vivo validation to confirm TUG1's therapeutic potential.
conclusionsLncRNA TUG1 attenuates high glucose-induced endocytic clearance dysfunction in HLSECs, potentially via regulating the Wnt/β-catenin pathway. As a key regulatory target for HLSEC endocytic function, TUG1 offers novel perspectives for understanding MAFLD's pathogenesis and developing targeted therapies.
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