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

OBJECTIVE

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 aims to explore the role and mechanism of PCBP1 in glucose and lipid metabolism dysregulation in GDM.

METHODS

To establish 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 cell counting kit-8(CCK-8) assay. Apoptotic activity was examined through Terminal deoxynucleotidyl transferase dutp nick end labeling (TUNEL) staining, and the expression levels of key proteins, including phosphorylated AKT (p-AKT), phosphorylated IRS1 (p-IRS1), PCBP1, transforming growth factor β-activated kinase 1(TAK1), and Peroxisome proliferator-activated receptor gamma (PPARγ), were analyzed through Western blotting.

RESULTS

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 PPARγ 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 PPARγ upregulation, while TAK1 overexpression negated these effects. Additionally, silencing PPARγ in TAK1-silenced cells reversed the metabolic improvements in IR-HepG2 cells, whereas overexpression of PPARγ mitigated the adverse effects of PCBP1 overexpression.

CONCLUSION

The foregoing findings demonstrate that PCBP1 exerts its effects on glucose and lipid metabolism in GDM via the TAK1/PPARγ signaling axis. Our study highlights the important function of the PCBP1/TAK1/PPARγ signaling pathway in mediating glucose and lipid metabolism in GDM, providing valuable insights into possible therapeutic targets for GDM treatment.