Giannotti Laura, Stanca Eleonora, Di Chiara Stanca Benedetta, Spedicato Francesco, Massaro Marika, Quarta Stefano, Del Rio Daniele, Mena Pedro, Siculella Luisa, Damiano Fabrizio
Department of Experimental Medicine (DiMeS), University of Salento, Lecce, 73100, Italy.
Institute of Clinical Physiology (IFC), National Research Council (CNR), Lecce, 73100, Italy.
Mol Nutr Food Res. 2024 Nov;68(21):e2400338. doi: 10.1002/mnfr.202400338. Epub 2024 Oct 6.
Type 2 diabetes and nonalcoholic fatty liver diseases (NAFLDs) are promoted by insulin resistance (IR), which alters lipid homeostasis in the liver. This study aims to investigate the effect of N-methylpyridinium (NMP), a bioactive alkaloid of coffee brew, on lipid metabolism in hepatocytes.
The effect of NMP in modulating lipid metabolism is evaluated at physiological concentrations in a diabetes cell model represented by HepG2 cells cultured in a high-glucose medium. Hyperglycemia triggers lipid droplet accumulation in cells and enhances the lipogenic gene expression, which is transactivated by sterol regulatory element binding protein-1 (SREBP-1). Lipid droplet accumulation alters the redox status and endoplasmic reticulum (ER) stress, leading to the activation of the unfolded protein response and antioxidative pathways by X-Box Binding Protein 1(XBP-1)/eukaryotic Initiation Factor 2 alpha (eIF2α) Protein Kinase RNA-Like ER Kinase and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. NMP induces the phosphorylation of AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase α (ACACA), and improves the redox status and ER homeostasis, essential steps to reduce lipogenesis and lipid droplet accumulation.
These results suggest that NMP may be beneficial for the management of T2D and NAFLD by ameliorating the cell oxidative and ER homeostasis and lipid metabolism.
2型糖尿病和非酒精性脂肪性肝病（NAFLD）由胰岛素抵抗（IR）引发，胰岛素抵抗会改变肝脏中的脂质稳态。本研究旨在探究咖啡冲泡液中的生物活性生物碱N-甲基吡啶鎓（NMP）对肝细胞脂质代谢的影响。
在以高糖培养基中培养的HepG2细胞为代表的糖尿病细胞模型中，评估生理浓度下NMP对脂质代谢的调节作用。高血糖会引发细胞内脂滴积累，并增强脂肪生成基因的表达，该表达由固醇调节元件结合蛋白-1（SREBP-1）反式激活。脂滴积累会改变氧化还原状态和内质网（ER）应激，分别导致X盒结合蛋白1（XBP-1）/真核起始因子2α（eIF2α）蛋白激酶样内质网激酶和核因子红细胞2相关因子2（NRF2）激活未折叠蛋白反应和抗氧化途径。NMP诱导AMP依赖蛋白激酶（AMPK）和乙酰辅酶A羧化酶α（ACACA）磷酸化，并改善氧化还原状态和内质网稳态，这是减少脂肪生成和脂滴积累的关键步骤。
这些结果表明，NMP可能通过改善细胞氧化和内质网稳态以及脂质代谢，对2型糖尿病和NAFLD的管理有益。
