Centre of General Practice, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China.
Department of Laboratory Medicine, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China.
Life Sci. 2024 Nov 15;357:123096. doi: 10.1016/j.lfs.2024.123096. Epub 2024 Oct 5.
Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism.
We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism.
Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway.
This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.
胰岛素抵抗（IR）是与 2 型糖尿病和代谢综合征相关的关键代谢紊乱。本研究探讨了黄嘌呤（Hx）作为一种嘌呤代谢物和尿酸前体，改善 IR 和调节肝葡萄糖和脂质代谢的潜力。
我们利用体外 IR-HepG2 细胞和体内饮食诱导的 IR 小鼠来研究 Hx 的影响。用 Hx 处理 HepG2 细胞，以评估其对葡萄糖生成和脂质沉积的影响。应用活性蛋白质谱（ABPP）来鉴定 Hx 靶蛋白及其潜在途径。在体内研究中，将 Hx 给予 IR 小鼠，然后评估与 IR 相关的指标，探讨其对肝葡萄糖和脂质代谢的潜在调节机制。
Hx 干预以剂量依赖的方式显著降低了 IR-HepG2 细胞中葡萄糖生成和脂质沉积，而不影响细胞活力。ABPP 鉴定了参与脂肪酸和丙酮酸代谢的关键 Hx 靶蛋白。在体内，Hx 治疗降低了 IR 的严重程度，表现为 HOMA-IR、空腹血糖和血清脂质谱降低。组织学评估证实了肝脂质沉积减少。机制研究表明，Hx 通过 AMPK/mTOR/PPARα 通路抑制肝糖异生和脂肪酸合成，促进脂肪酸氧化。
本研究描绘了 Hx 调节肝代谢的新作用，为 IR 及相关代谢紊乱提供了一种潜在的治疗策略。这些发现为进一步研究嘌呤代谢物在代谢调节中的作用及其临床意义提供了基础。
