Xia Qing-Song, Wu Fan, Wu Wen-Bin, Dong Hui, Huang Zhao-Yi, Xu Lijun, Lu Fu-Er, Gong Jing
Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Biomed Pharmacother. 2022 Jun;150:112955. doi: 10.1016/j.biopha.2022.112955. Epub 2022 Apr 13.
Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy.
多项研究记录了缺氧和神经酰胺对脂质和葡萄糖代谢的影响，从而导致胰岛素抵抗。然而，神经酰胺在肝脏缺氧和肝脏胰岛素抵抗中的作用仍有待阐明。本研究旨在探讨高脂饮食（HFD）喂养的小鼠中缺氧、神经酰胺合成与肝脏胰岛素抵抗之间的关系。鉴于通过分子对接确定的缺氧诱导因子2α（HIF-2α）与小檗碱之间的相互作用，本研究还评估了小檗碱对HIF-2α-神经酰胺-胰岛素抵抗途径的药理作用。在研究的初步阶段，随着2型糖尿病（T2DM）的发展，由于HIF-2α积累增加，观察到肝脏缺氧逐渐加重以及神经酰胺水平各异。对动物和细胞模型的脂质组学分析表明，小檗碱可减少缺氧诱导的神经酰胺生成，并减轻神经酰胺诱导的胰岛素抵抗。本研究为神经酰胺在肝脏缺氧和胰岛素抵抗中的作用提供了及时且必要的证据。它也有助于更好地理解小檗碱在改善T2DM治疗中的缺氧和胰岛素抵抗方面的药理作用。
