Chao Zhang1,2, Jianjun Deng3, Dan Liu2, Xingxia Tuo2, Lei Xiao1, Baochang Lai1, Qinyu Yao1, Jia Liu1, Haixia Yang2, Nanping Wang1,4. 1. Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China. 2. Department of Nutrition and Food Safety, College of Public Health, Xi'an Jiaotong University, Xi'an, China. 3. Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an, China. 4. The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
Abstract
BACKGROUND AND PURPOSE: Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the underlying mechanism is unclear. The present study aimed to investigate the effects of nuciferine on lipid and glucose metabolism in a murine model of Type 2 diabetes mellitus (T2DM) and to determine the underlying mechanisms of these effects. EXPERIMENTAL APPROACH: A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with nuciferine in their food. The underlying mechanism of the anti-steatotic effect of nuciferine was further explored in HepG2 hepatocytes cultured with palmitic acid. Major signalling profiles involved in fatty acid oxidation were then evaluated, using Western blot, RT-qPCR and si-RNA techniques, along with immunohistochemistry. KEY RESULTS: Nuciferine restored impaired glucose tolerance and insulin resistance in diabetic mice. Hepatic levels of total cholesterol, triglycerides and LDL were decreased, as were the number of lipid droplets, by nuciferine treatment. Furthermore, nuciferine up-regulated β-oxidation related genes in livers of diabetic mice. Luciferase reporter cell assay showed that nuciferine directly reversed palmitic acid-induced inhibition of PPARα transcriptional activity. Silencing PPARγ coactivator-1α (PGC1α) expression in HepG2 cells abolished the effects of nuciferine in accelerating β-oxidation. CONCLUSIONS AND IMPLICATIONS: Nuciferine improved lipid profile and attenuated hepatic steatosis in HFD/STZ-induced diabetic mice by activating the PPARα/PGC1α pathway. Nuciferine may be a potentially important candidate in improving hepatic steatosis and the management of T2DM.
BACKGROUND AND PURPOSE:Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the underlying mechanism is unclear. The present study aimed to investigate the effects of nuciferine on lipid and glucose metabolism in a murine model of Type 2 diabetes mellitus (T2DM) and to determine the underlying mechanisms of these effects. EXPERIMENTAL APPROACH: A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabeticmice were treated with nuciferine in their food. The underlying mechanism of the anti-steatotic effect of nuciferine was further explored in HepG2 hepatocytes cultured with palmitic acid. Major signalling profiles involved in fatty acid oxidation were then evaluated, using Western blot, RT-qPCR and si-RNA techniques, along with immunohistochemistry. KEY RESULTS:Nuciferine restored impaired glucose tolerance and insulin resistance in diabeticmice. Hepatic levels of total cholesterol, triglycerides and LDL were decreased, as were the number of lipid droplets, by nuciferine treatment. Furthermore, nuciferine up-regulated β-oxidation related genes in livers of diabeticmice. Luciferase reporter cell assay showed that nuciferine directly reversed palmitic acid-induced inhibition of PPARα transcriptional activity. Silencing PPARγ coactivator-1α (PGC1α) expression in HepG2 cells abolished the effects of nuciferine in accelerating β-oxidation. CONCLUSIONS AND IMPLICATIONS: Nuciferine improved lipid profile and attenuated hepatic steatosis in HFD/STZ-induced diabeticmice by activating the PPARα/PGC1α pathway. Nuciferine may be a potentially important candidate in improving hepatic steatosis and the management of T2DM.
Authors: Kfir Sharabi; Hua Lin; Clint D J Tavares; John E Dominy; Joao Paulo Camporez; Rachel J Perry; Roger Schilling; Amy K Rines; Jaemin Lee; Marc Hickey; Melissa Bennion; Michelle Palmer; Partha P Nag; Joshua A Bittker; José Perez; Mark P Jedrychowski; Umut Ozcan; Steve P Gygi; Theodore M Kamenecka; Gerald I Shulman; Stuart L Schreiber; Patrick R Griffin; Pere Puigserver Journal: Cell Date: 2017-03-23 Impact factor: 41.582