{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:18:04Z","timestamp":1791980284964,"version":"4.4.0"},"reference-count":80,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T00:00:00Z","timestamp":1589587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009888","name":"Regione Toscana","doi-asserted-by":"publisher","award":["3242"],"award-info":[{"award-number":["3242"]}],"id":[{"id":"10.13039\/501100009888","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["66783"],"award-info":[{"award-number":["66783"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA026972"],"award-info":[{"award-number":["AA026972"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA026978"],"award-info":[{"award-number":["AA026978"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA026264"],"award-info":[{"award-number":["AA026264"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30DK120531"],"award-info":[{"award-number":["P30DK120531"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy\/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation.<\/jats:p>","DOI":"10.3390\/cells9051237","type":"journal-article","created":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T11:34:14Z","timestamp":1589801654000},"page":"1237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH"],"prefix":"10.3390","volume":"9","author":[{"given":"Francesca","family":"Zanieri","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine and Center of Excellence \u201cDENOthe\u201d, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-6614","authenticated-orcid":false,"given":"Ana","family":"Levi","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Montefusco","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Longato","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"De Chiara","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Frenguelli","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2443-3631","authenticated-orcid":false,"given":"Sara","family":"Omenetti","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine and Center of Excellence \u201cDENOthe\u201d, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4926-0121","authenticated-orcid":false,"given":"Fausto","family":"Andreola","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7598-7319","authenticated-orcid":false,"given":"Tu Vinh","family":"Luong","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"},{"name":"Department of Cellular Pathology, Royal Free Hospital, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Massey","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gastroenterology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Caballeria","sequence":"additional","affiliation":[{"name":"Hepatology, Hospital Cl\u00ednic, IDIBAPS, CIBERehd, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantino","family":"Fondevila","sequence":"additional","affiliation":[{"name":"Liver Transplant Unit, Department of Surgery, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sriram S","family":"Shanmugavelandy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5170-3951","authenticated-orcid":false,"given":"Todd","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Mazza","sequence":"additional","affiliation":[{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josepmaria","family":"Argemi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Bataller","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gastroenterology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren Ashley","family":"Cowart","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University, Richmond, VA 23219, USA"},{"name":"Hunter Holmes McGuire VA Medical Center, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Kester","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA"},{"name":"Department of Pharmacology, University of Virginia School of Medicine, P.O. Box 800735, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Pinzani","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine and Center of Excellence \u201cDENOthe\u201d, University of Florence, 50134 Florence, Italy"},{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"},{"name":"Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9440-0571","authenticated-orcid":false,"given":"Krista","family":"Rombouts","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine and Center of Excellence \u201cDENOthe\u201d, University of Florence, 50134 Florence, Italy"},{"name":"Institute for Liver &amp; Digestive Health, Royal Free, University College London UCL, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.jhep.2012.12.005","article-title":"The burden of liver disease in Europe: A review of available epidemiological data","volume":"58","author":"Blachier","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1053\/j.gastro.2014.07.056","article-title":"Pathological features of fatty liver disease","volume":"147","author":"Yeh","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.bpg.2011.02.010","article-title":"Fibrosis in alcoholic and nonalcoholic steatohepatitis","volume":"25","author":"Bataller","year":"2011","journal-title":"Best. Pract. Res. Clin. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Drescher, H.K., Weiskirchen, S., and Weiskirchen, R. (2019). Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Cells, 8.","DOI":"10.3390\/cells8080845"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1007\/s11901-018-0425-7","article-title":"Pathogenesis of NASH: The Impact of Multiple Pathways","volume":"17","author":"Noureddin","year":"2018","journal-title":"Curr. Hepatol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1172\/JCI200422422","article-title":"Molecular mediators of hepatic steatosis and liver injury","volume":"114","author":"Browning","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.biocel.2008.10.027","article-title":"Non-alcoholic steatohepatitis and animal models: Understanding the human disease","volume":"41","author":"Embade","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1002\/hep.23229","article-title":"The plasma lipidomic signature of nonalcoholic steatohepatitis","volume":"50","author":"Puri","year":"2009","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"726","DOI":"10.2174\/138920112799857558","article-title":"Non-alcoholic steatohepatitis: New insights from OMICS studies","volume":"13","author":"Martel","year":"2012","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_10","first-page":"71","article-title":"Pathogenesis of non-alcoholic fatty liver disease","volume":"103","author":"Dowman","year":"2010","journal-title":"QJM Mon. J. Assoc. Phys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jbior.2018.11.004","article-title":"Alcoholic and non-alcoholic fatty liver disease: Focus on ceramide","volume":"70","year":"2018","journal-title":"Adv. Biol. Regul."},{"key":"ref_12","first-page":"1074","article-title":"Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease","volume":"34","author":"Kurek","year":"2014","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"41479","DOI":"10.18632\/oncotarget.6286","article-title":"Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis","volume":"6","author":"Martinez","year":"2015","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.cmet.2014.10.007","article-title":"CerS2 Haploinsufficiency Inhibits beta-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance","volume":"20","author":"Raichur","year":"2014","journal-title":"Cell Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.cmet.2014.08.002","article-title":"Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance","volume":"20","author":"Turpin","year":"2014","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1089\/neu.2014.3497","article-title":"Spinal cord injury causes chronic liver pathology in rats","volume":"32","author":"Sauerbeck","year":"2015","journal-title":"J. Neurotrauma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.biochi.2018.07.021","article-title":"Sphingolipid metabolism in non-alcoholic fatty liver diseases","volume":"159","author":"Regnier","year":"2019","journal-title":"Biochimie"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.4161\/cc.8.8.8161","article-title":"A new take on ceramide: Starving cells by cutting off the nutrient supply","volume":"8","author":"Guenther","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4222","DOI":"10.1172\/JCI57144","article-title":"Ceramides as modulators of cellular and whole-body metabolism","volume":"121","author":"Bikman","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"ElAzzouny, M.A., Evans, C.R., Burant, C.F., and Kennedy, R.T. (2015). Metabolomics Analysis Reveals that AICAR Affects Glycerolipid, Ceramide and Nucleotide Synthesis Pathways in INS-1 Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129029"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"337","DOI":"10.2337\/db08-1228","article-title":"Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance","volume":"58","author":"Haus","year":"2009","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1073\/pnas.97.4.1784","article-title":"Lipotoxic heart disease in obese rats: Implications for human obesity","volume":"97","author":"Zhou","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"G1004","DOI":"10.1152\/ajpgi.00482.2009","article-title":"Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels","volume":"298","author":"Liangpunsakul","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1128\/MCB.00677-14","article-title":"Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance","volume":"34","author":"Meakin","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1089\/ars.2012.5116","article-title":"The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice","volume":"20","author":"Mo","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1128\/MCB.00118-16","article-title":"AMPK Facilitates Nuclear Accumulation of Nrf2 by Phosphorylating at Serine 550","volume":"36","author":"Joo","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"597134","DOI":"10.1155\/2015\/597134","article-title":"The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism","volume":"2015","author":"Chambel","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1189\/jlb.0108076","article-title":"Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide","volume":"83","author":"Sun","year":"2008","journal-title":"J. Leukoc Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s12010-008-8505-8","article-title":"Effect of ceramide on mesenchymal stem cell differentiation toward adipocytes","volume":"160","author":"Xu","year":"2010","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"911","DOI":"10.2174\/187152011797655177","article-title":"Ceramide-based therapeutics for the treatment of cancer","volume":"11","author":"Barth","year":"2011","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4967","DOI":"10.1021\/nn102324e","article-title":"Nanoparticulate alternatives for drug delivery","volume":"4","author":"Adair","year":"2010","journal-title":"ACS Nano"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1515\/hsz-2015-0129","article-title":"Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic","volume":"396","author":"Kester","year":"2015","journal-title":"Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ishii, T., and Warabi, E. (2019). Mechanism of Rapid Nuclear Factor-E2-Related Factor 2 (Nrf2) Activation via Membrane-Associated Estrogen Receptors: Roles of NADPH Oxidase 1, Neutral Sphingomyelinase 2 and Epidermal Growth Factor Receptor (EGFR). Antioxidants, 8.","DOI":"10.3390\/antiox8030069"},{"key":"ref_34","first-page":"893","article-title":"Ceramide, an apoptotic rheostat, inhibits CCAAT\/enhancer binding protein-beta and NF-E2-related factor-2 activation: The role in glutathione S-transferase A2 gene repression","volume":"32","author":"Park","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuint.2016.02.004","article-title":"Short-chain C2 ceramide induces heme oxygenase-1 expression by upregulating AMPK and MAPK signaling pathways in rat primary astrocytes","volume":"94","author":"Jung","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1038\/s41467-019-11004-3","article-title":"Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis","volume":"10","author":"Argemi","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.1158\/1078-0432.CCR-04-1770","article-title":"Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma","volume":"11","author":"Stover","year":"2005","journal-title":"Clin. Cancer Res. An Off. J. Am. Assoc. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/labinvest.2009.112","article-title":"Curcumin limits the fibrogenic evolution of experimental steatohepatitis","volume":"90","author":"Vizzutti","year":"2010","journal-title":"Lab. Invest."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1172\/JCI18212","article-title":"NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis","volume":"112","author":"Bataller","year":"2003","journal-title":"J. Clin. Invest."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nprot.2015.017","article-title":"High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers","volume":"10","author":"Mederacke","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/978-1-4939-3170-5_17","article-title":"Determination and Characterization of Tetraspanin-Associated Phosphoinositide-4 Kinases in Primary and Neoplastic Liver Cells","volume":"1376","author":"Rombouts","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Marrone, G., De Chiara, F., Bottcher, K., Levi, A., Dhar, D., Longato, L., Mazza, G., Zhang, Z., Marrali, M., and Iglesias, A.F. (2018). The AMPK-v-ATPase-pH axis: A key regulator of the pro-fibrogenic phenotype of human hepatic stellate cells. Hepatology.","DOI":"10.1002\/hep.30029"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.freeradbiomed.2016.11.036","article-title":"Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro","volume":"102","author":"Longato","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jalan, R., De Chiara, F., Balasubramaniyan, V., Andreola, F., Khetan, V., Malago, M., Pinzani, M., Mookerjee, R.P., and Rombouts, K. (2015). Ammonia produces pathological changes in human hepatic stellate cells and is a target of therapy of portal hypertension. J. Hepatol.","DOI":"10.1016\/S0168-8278(15)30652-8"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1194\/jlr.D700041-JLR200","article-title":"Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics","volume":"49","author":"Matyash","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1146\/annurev-pharmtox-010818-021856","article-title":"Modulating NRF2 in Disease: Timing Is Everything","volume":"59","author":"Dodson","year":"2019","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1053\/j.gastro.2007.10.039","article-title":"Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease","volume":"134","author":"Puri","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1172\/JCI86013","article-title":"Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance","volume":"126","author":"Petersen","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1093\/bioinformatics\/btu383","article-title":"Literome: PubMed-scale genomic knowledge base in the cloud","volume":"30","author":"Poon","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.bbrc.2019.01.024","article-title":"Overexpression of Interleukin-15 exhibits improved glucose tolerance and promotes GLUT4 translocation via AMP-Activated protein kinase pathway in skeletal muscle","volume":"509","author":"Fujimoto","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11596-019-1997-3","article-title":"Berberine Ameliorates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Rats via Activation of SIRT3\/AMPK\/ACC Pathway","volume":"39","author":"Zhang","year":"2019","journal-title":"Curr. Med. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.freeradbiomed.2015.06.007","article-title":"The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1","volume":"88","author":"Rhee","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cmet.2006.03.007","article-title":"The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis","volume":"3","author":"Li","year":"2006","journal-title":"Cell Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.jhep.2005.08.026","article-title":"Mice heterozygous for the Mdr2 gene demonstrate decreased PEMT activity and diminished steatohepatitis on the MCD diet","volume":"44","author":"Igolnikov","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10355","DOI":"10.3390\/ijms140510355","article-title":"Ultraviolet (UV) and hydrogen peroxide activate ceramide-ER stress-AMPK signaling axis to promote retinal pigment epithelium (RPE) cell apoptosis","volume":"14","author":"Yao","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41419-019-2214-9","article-title":"Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steatohepatitis by reducing oxidative stress","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"407","DOI":"10.4161\/auto.5.3.7809","article-title":"Ceramide-induced starvation triggers homeostatic autophagy","volume":"5","author":"Peralta","year":"2009","journal-title":"Autophagy"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Simon, J., Ouro, A., Ala-Ibanibo, L., Presa, N., Delgado, T.C., and Martinez-Chantar, M.L. (2019). Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010040"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.cmet.2014.10.017","article-title":"C16:0-ceramide signals insulin resistance","volume":"20","author":"Hla","year":"2014","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1124\/dmd.107.019679","article-title":"Rapid distribution of liposomal short-chain ceramide in vitro and in vivo","volume":"36","author":"Zolnik","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1182\/blood-2010-02-271080","article-title":"Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia","volume":"116","author":"Liu","year":"2010","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1136\/gut.2010.216671","article-title":"Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma","volume":"60","author":"Tagaram","year":"2011","journal-title":"Gut"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1124\/jpet.103.054056","article-title":"Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells","volume":"307","author":"Stover","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1053\/j.gastro.2017.10.050","article-title":"Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice","volume":"154","author":"Li","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/CS20110060","article-title":"Methionine and protein metabolism in non-alcoholic steatohepatitis: Evidence for lower rate of transmethylation of methionine","volume":"121","author":"Kalhan","year":"2011","journal-title":"Clin. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1111\/j.1872-034X.2012.00976.x","article-title":"Plasma free choline is a novel non-invasive biomarker for early-stage non-alcoholic steatohepatitis: A multi-center validation study","volume":"42","author":"Imajo","year":"2012","journal-title":"Hepatol. Res. Off. J. Japan Soc. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1159\/000282097","article-title":"Animal models of non-alcoholic steatohepatitis: Of mice and man","volume":"28","author":"Schattenberg","year":"2010","journal-title":"Dig. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/mnfr.201100524","article-title":"Molecular alterations in hepatocarcinogenesis induced by dietary methyl deficiency","volume":"56","author":"Pogribny","year":"2012","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1097\/MCO.0b013e3283600d46","article-title":"Choline\u2019s role in maintaining liver function: New evidence for epigenetic mechanisms","volume":"16","author":"Mehedint","year":"2013","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/j.1753-4887.2009.00246.x","article-title":"Choline: An essential nutrient for public health","volume":"67","author":"Zeisel","year":"2009","journal-title":"Nutr. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41419-020-2295-5","article-title":"Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease","volume":"11","author":"Han","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1042\/CS20110515","article-title":"Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis","volume":"123","author":"Galastri","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Tang, X., Keenan, M.M., Wu, J., Lin, C.A., Dubois, L., Thompson, J.W., Freedland, S.J., Murphy, S.K., and Chi, J.T. (2015). Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005158"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.cmet.2019.10.011","article-title":"Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity","volume":"30","author":"Sica","year":"2019","journal-title":"Cell Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"787","DOI":"10.3389\/fphys.2017.00787","article-title":"Brain Ceramide Metabolism in the Control of Energy Balance","volume":"8","author":"Lopez","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1042\/bst0310202","article-title":"Malonyl-CoA and AMP-activated protein kinase (AMPK): Possible links between insulin resistance in muscle and early endothelial cell damage in diabetes","volume":"31","author":"Ruderman","year":"2003","journal-title":"Biochem. Soc. Trans."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/978-1-4419-6741-1_5","article-title":"Tales and mysteries of the enigmatic sphingomyelin synthase family","volume":"688","author":"Holthuis","year":"2010","journal-title":"Adv. Exp. Med. Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/5\/1237\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:29:35Z","timestamp":1760174975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/5\/1237"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,16]]},"references-count":80,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["cells9051237"],"URL":"https:\/\/doi.org\/10.3390\/cells9051237","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,16]]}}}