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bioRxiv · 10.1101/2024.12.28.630638

Suppression of PCBP1 Enhances PPARgamma via TAK1 Modulation to Improve Glycemic and Lipid Metabolism Disorders in Gestational Diabetes Mellitus

Xia, X.·Chen, Y.
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Abstract

Gestational diabetes mellitus (GDM) affects the health of pregnant women and their fetuses. Poly(C)-binding protein 1 (PCBP1), a multifunctional RNA-binding protein, is pivotal in maintaining cytosolic iron homeostasis. This study sheds light on the role and mechanism of PCBP1 in glucose and lipid metabolism dysregulation in GDM via a high-fat diet-induced GDM mouse model and a palmitic acid (PA)-triggered insulin resistance(IR) model in HepG2 cells. Glucose tolerance and insulin tolerance tests were performed in GDM mice, with lipid metabolism evaluated via hematoxylin-eosin (HE) staining, Oil Red O staining, as well as biochemical assay kits. Glucose content was quantified using the glucose oxidase method, while cell viability was evaluated trough the CCK-8 assay. Apoptotic activity was examined through TUNEL staining, and the expression levels of key proteins, including phosphorylated AKT (p-AKT), phosphorylated IRS1 (p-IRS1), PCBP1, TAK1, and PPAR{gamma}, were analyzed through Western blotting. The results demonstrated that GDM mice exhibited profound glucose and lipid metabolism disorders, characterized by significant lipid droplet accumulation in hepatic cells and disrupted insulin signaling pathways. Furthermore, hepatic expression of PCBP1 and TAK1 was notably upregulated, whereas PPAR{gamma} expression was significantly reduced. In vitro experiments revealed that silencing PCBP1 alleviated glucose and lipid metabolism abnormalities and improved insulin signaling in PA-induced insulin-resistant HepG2 (IR-HepG2) cells. This intervention also enhanced cell viability and suppressed apoptosis. Further mechanistic studies indicated that inhibition of TAK1 expression facilitated PPAR{gamma} upregulation, while TAK1 overexpression negated these effects. Additionally, silencing PPAR{gamma} in TAK1-silenced cells reversed the metabolic improvements in IR-HepG2 cells, whereas overexpression of PPAR{gamma} mitigated the adverse effects of PCBP1 overexpression. The foregoing findings demonstrate that PCBP1 exerts its effects on glucose and lipid metabolism in GDM via the TAK1/PPAR{gamma} signaling axis. Our study highlights the important function of the PCBP1/TAK1/PPAR{gamma} signaling pathway in mediating glucose and lipid metabolism in GDM, providing valuable insights into possible therapeutic targets for GDM treatment.

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Xia, X., Chen, Y.. 2024-12-30. Suppression of PCBP1 Enhances PPARgamma via TAK1 Modulation to Improve Glycemic and Lipid Metabolism Disorders in Gestational Diabetes Mellitus. https://doi.org/10.1101/2024.12.28.630638

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