Abstract
Background: NXT629, a PPAR-alpha antagonist, exerts widespread effects in many diseases; however, its function and relevant mechanism in cholesterol gallstones (CG) remain largely unknown. Methods: Male C57BL/6 J mice were fed a regular diet or lithogenic diet (LD), followed by treatment with intraperitoneal injection of NXT629. H&E staining was performed to analyze hepatic pathological changes, and Oil red O staining was conducted to detect lipid accumulation. Concentrations of total cholesterol (TC), triglyceride (TG), phospholipids (PL), total bile acids (TBA), and cholesterol saturation index (CSI) in both bile and serum were analyzed using commercially available kits. The mRNA expressions of ABCG5/8, CYP7A1, CYP7B1, PPAR-α, and ABCB11 in mouse liver tissues were measured by qRT-PCR assay. Overexpression of glycerol-3-phosphate acyltransferase mitochondrial (GPAM) was constructed to investigate the molecular mechanism of NXT629 in CG. Results: NXT629 could prevent the formation of cholesterol gallstones (CG) and improve lipid metabolic disorders in mice fed a lithogenic diet (LD). Treatment with NXT629 significantly reduced the levels of ABCG5, ABCG8, and ABCB11, while increasing the levels of CYP7A1 and CYP7B1 in the LD group. Additionally, NXT629 treatment downregulated GPAM expression in hepatic tissue from LD-fed mice. Overexpression of GPAM partially counteracted the beneficial effects of NXT629 on CG formation, lipid metabolic disorders, and lipid-related gene expressions. Conclusion: NXT629 can inhibit CG formation, improve lipid metabolism disorders and cholesterol homeostasis by inhibiting GPAM expression, suggesting that NXT629 may serve as a potential therapeutic strategy for cholesterol stones prevention and treatment.