Nuciferine protects against high-fat diet-induced hepatic steatosis and insulin resistance via activating TFEB-mediated autophagy–lysosomal pathway

Sheth, 1997, Nonalcoholic steatohepatitis, Ann Intern Med, 126, 137, 10.7326/0003-4819-126-2-199701150-00008 Ludwig, 1980, Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease, Mayo Clin Proc, 55, 434 Czaja, 2016, Function of autophagy in nonalcoholic fatty liver disease, Dig Dis Sci, 61, 1304, 10.1007/s10620-015-4025-x Sinha, 2014, Caffeine stimulates hepatic lipid metabolism by the autophagy–lysosomal pathway in mice, Hepatology, 59, 1366, 10.1002/hep.26667 Miyagawa, 2016, Lipid-induced endoplasmic reticulum stress impairs selective autophagy at the step of autophagosome–lysosome fusion in hepatocytes, Am J Pathol, 186, 1861, 10.1016/j.ajpath.2016.03.003 Wang, 2018, Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis, FASEB J, 32, 37, 10.1096/fj.201601393R Yang, 2010, Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance, Cell Metabol, 11, 467, 10.1016/j.cmet.2010.04.005 Farah, 2016, Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency, J Hepatol, 64, 370, 10.1016/j.jhep.2015.10.008 Settembre, 2011, TFEB links autophagy to lysosomal biogenesis, Science, 332, 1429, 10.1126/science.1204592 Sardiello, 2009, A gene network regulating lysosomal biogenesis and function, Science, 325, 473, 10.1126/science.1174447 Settembre, 2012, A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB, EMBO J, 31, 1095, 10.1038/emboj.2012.32 Martina, 2012, MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB, Autophagy, 8, 903, 10.4161/auto.19653 Roczniak-Ferguson, 2012, The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis, Sci Signal, 5, ra42, 10.1126/scisignal.2002790 Garami, 2003, Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2, Mol Cell, 11, 1457, 10.1016/S1097-2765(03)00220-X Kim, 2008, Regulation of TORC1 by Rag GTPases in nutrient response, Nat Cell Biol, 10, 935, 10.1038/ncb1753 Sancak, 2008, The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1, Science, 320, 1496, 10.1126/science.1157535 Long, 2005, Rheb binds and regulates the mTOR kinase, Curr Biol, 15, 702, 10.1016/j.cub.2005.02.053 Sancak, 2010, Ragulator–Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids, Cell, 141, 290, 10.1016/j.cell.2010.02.024 Su, 2017, Hybrid structure of the RagA/C-Ragulator mTORC1 activation complex, Mol Cell, 68, 835, 10.1016/j.molcel.2017.10.016 Yonehara, 2017, Structural basis for the assembly of the Ragulator–Rag GTPase complex, Nat Commun, 8, 1625, 10.1038/s41467-017-01762-3 Zhang, 2017, Structural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1, Nat Commun, 8, 1394, 10.1038/s41467-017-01567-4 Bar-Peled, 2012, Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1, Cell, 150, 1196, 10.1016/j.cell.2012.07.032 Kim, 2017, Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition, Autophagy, 13, 1767, 10.1080/15548627.2017.1356977 Zhang, 2018, Dynamic MTORC1-TFEB feedback signaling regulates hepatic autophagy, steatosis and liver injury in long-term nutrient oversupply, Autophagy, 14, 1779, 10.1080/15548627.2018.1490850 Pastore, 2016, TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages, Autophagy, 12, 1240, 10.1080/15548627.2016.1179405 Settembre, 2013, TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop, Nat Cell Biol, 15, 647, 10.1038/ncb2718 Chao, 2018, Impaired TFEB-mediated lysosome biogenesis and autophagy promote chronic ethanol-induced liver injury and steatosis in mice, Gastroenterology, 155, 865, 10.1053/j.gastro.2018.05.027 Lin, 2013, Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice, J Hepatol, 58, 993, 10.1016/j.jhep.2013.01.011 Liu, 2014, Antioxidant and anticancer aporphine alkaloids from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena, Molecules, 19, 17829, 10.3390/molecules191117829 Guo, 2013, Nuciferine prevents hepatic steatosis and injury induced by a high-fat diet in hamsters, PLoS One, 8 Cui, 2020, Untargeted metabolomic analysis of the effects and mechanism of nuciferine treatment on rats with nonalcoholic fatty liver disease, Front Pharmacol, 11, 858, 10.3389/fphar.2020.00858 Wang, 2016, Nuciferine alleviates renal injury by inhibiting inflammatory responses in fructose-fed rats, J Agric Food Chem, 64, 7899, 10.1021/acs.jafc.6b03031 Zhang, 2018, Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through a PPARα/PPARγ coactivator-1α pathway, Br J Pharmacol, 175, 4218, 10.1111/bph.14482 Medina, 2015, Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB, Nat Cell Biol, 17, 288, 10.1038/ncb3114 Napolitano, 2020, A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome, Nature, 585, 597, 10.1038/s41586-020-2444-0 Livak, 2001, Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method, Methods, 25, 402, 10.1006/meth.2001.1262 Bustin, 2009, The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments, Clin Chem, 55, 611, 10.1373/clinchem.2008.112797 Li, 2020, Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice, Br J Pharmacol, 177, 3591, 10.1111/bph.15083 Martinez Molina, 2013, Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay, Science, 341, 84, 10.1126/science.1233606 Mu, 2017, Structural insight into the Ragulator complex which anchors mTORC1 to the lysosomal membrane, Cell Discov, 3, 17049, 10.1038/celldisc.2017.49 Seeliger, 2010, Ligand docking and binding site analysis with PyMOL and Autodock/Vina, J Comput Aided Mol Des, 24, 417, 10.1007/s10822-010-9352-6 Phillips, 2020, Scalable molecular dynamics on CPU and GPU architectures with NAMD, J Chem Phys, 153, 10.1063/5.0014475 Yang, 2021, Insight into the dual inhibitory mechanism of verbascoside targeting serine/threonine phosphatase Stp1 against Staphylococcus aureus, Eur J Pharmaceut Sci, 157, 105628, 10.1016/j.ejps.2020.105628 Ballabio, 2020, Lysosomes as dynamic regulators of cell and organismal homeostasis, Nat Rev Mol Cell Biol, 21, 101, 10.1038/s41580-019-0185-4 Martina, 2013, Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes, J Cell Biol, 200, 475, 10.1083/jcb.201209135 Schweitzer, 2015, Disruption of the Rag–Ragulator complex by c17orf59 inhibits mTORC1, Cell Rep, 12, 1445, 10.1016/j.celrep.2015.07.052 Kim, 2013, Lotus leaf alleviates hyperglycemia and dyslipidemia in animal model of diabetes mellitus, Nutr Res Pract, 7, 166, 10.4162/nrp.2013.7.3.166 Khan, 2019, Modulation of insulin resistance in nonalcoholic fatty liver disease, Hepatology, 70, 711, 10.1002/hep.30429 Pastore, 2017, TFE3 regulates whole-body energy metabolism in cooperation with TFEB, EMBO Mol Med, 9, 605, 10.15252/emmm.201607204 Thelen, 2017, Emerging roles for the lysosome in lipid metabolism, Trends Cell Biol, 27, 833, 10.1016/j.tcb.2017.07.006 Trivedi, 2020, Loss of function of transcription factor EB remodels lipid metabolism and cell death pathways in the cardiomyocyte, Biochim Biophys Acta Mol Basis Dis, 1866, 165832, 10.1016/j.bbadis.2020.165832 Friedman, 2018, Mechanisms of NAFLD development and therapeutic strategies, Nat Med, 24, 908, 10.1038/s41591-018-0104-9 Wu, 2018, Alisol A 24-acetate ameliorates nonalcoholic steatohepatitis by inhibiting oxidative stress and stimulating autophagy through the AMPK/mTOR pathway, Chem Biol Interact, 291, 111, 10.1016/j.cbi.2018.06.005 Ao, 2020, Liraglutide ameliorates lipotoxicity-induced inflammation through the mTORC1 signalling pathway, Peptides, 133, 170375, 10.1016/j.peptides.2020.170375 Su, 2018, Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state, Free Radic Biol Med, 126, 269, 10.1016/j.freeradbiomed.2018.08.024 Saxton, 2017, mTOR Signaling in growth, metabolism, and disease, Cell, 168, 960, 10.1016/j.cell.2017.02.004 Sengupta, 2010, mTORC1 controls fasting-induced ketogenesis and its modulation by ageing, Nature, 468, 1100, 10.1038/nature09584 Yoo, 2019, Lotus leaf ethanol extract and nuciferine suppress adipocyte differentiation by regulating Akt–mTORC1 signaling in 3T3-L1 cells, J Food Nutr Res, 7, 688, 10.12691/jfnr-7-10-1 Kim, 2015, mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation, Mol Cell, 57, 207, 10.1016/j.molcel.2014.11.013 Kim, 2011, AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1, Nat Cell Biol, 13, 132, 10.1038/ncb2152 Ganley, 2009, ULK1.ATG13. FIP200 complex mediates mTOR signaling and is essential for autophagy, J Biol Chem, 284, 12297, 10.1074/jbc.M900573200 Horton, 2002, SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver, J Clin Invest, 109, 1125, 10.1172/JCI0215593 Porstmann, 2008, SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth, Cell Metabol, 8, 224, 10.1016/j.cmet.2008.07.007