{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T09:44:26Z","timestamp":1789897466506,"version":"4.0.1"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,7,26]],"date-time":"2017-07-26T00:00:00Z","timestamp":1501027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31470768"],"award-info":[{"award-number":["31470768"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31630037"],"award-info":[{"award-number":["31630037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31670830"],"award-info":[{"award-number":["31670830"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81321062"],"award-info":[{"award-number":["81321062"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2014CB542300"],"award-info":[{"award-number":["2014CB542300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Strategic Priority Research Program of the Chinese Academy of Sciences","award":["XDB19000000"],"award-info":[{"award-number":["XDB19000000"]}]},{"name":"the Strategic Priority Research Program of the Chinese Academy of Sciences","award":["XDA12030204"],"award-info":[{"award-number":["XDA12030204"]}]},{"name":"the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences","award":["2014KIP106"],"award-info":[{"award-number":["2014KIP106"]}]},{"name":"the CAS\/SAFEA International Partnership Program for Creative Research Teams"},{"name":"the Frontier Science of Chinese Academy of Sciences Key Research Projects","award":["QYZDJ-SSW-SMC022"],"award-info":[{"award-number":["QYZDJ-SSW-SMC022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Hemin is a breakdown product of hemoglobin. It has been reported that the injection of hemin improves lipid metabolism and insulin sensitivity in various genetic models. However, the effect of hemin supplementation in food on lipid metabolism and insulin sensitivity is still unclear, and whether hemin directly affects cellular insulin sensitivity is yet to be elucidated. Here we show that hemin enhances insulin-induced phosphorylation of insulin receptors, Akt, Gsk3\u03b2, FoxO1 and cytoplasmic translocation of FoxO1 in cultured primary hepatocytes under insulin-resistant conditions. Furthermore, hemin diminishes the accumulation of triglyceride and increases in free fatty acid content in primary hepatocytes induced by palmitate. Oral administration of hemin decreases body weight, energy intake, blood glucose and triglyceride levels, and improves insulin and glucose tolerance as well as hepatic insulin signaling and hepatic steatosis in male mice fed a high-fat diet. In addition, hemin treatment decreases the mRNA and protein levels of some hepatic genes involved in lipogenic regulation, fatty acid synthesis and storage, and increases the mRNA level and enzyme activity of CPT1 involved in fatty acid oxidation. These data demonstrate that hemin can improve lipid metabolism and insulin sensitivity in both cultured hepatocytes and mice fed a high-fat diet, and show the potential beneficial effects of hemin from food on lipid and glucose metabolism.<\/jats:p>","DOI":"10.3390\/nu9080805","type":"journal-article","created":{"date-parts":[[2017,7,26]],"date-time":"2017-07-26T11:45:01Z","timestamp":1501069501000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hemin Improves Insulin Sensitivity and Lipid Metabolism in Cultured Hepatocytes and Mice Fed a High-Fat Diet"],"prefix":"10.3390","volume":"9","author":[{"given":"Yi","family":"Luan","sequence":"first","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghong","family":"Yan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuangao","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhishui","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hejin","family":"Lai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Ying","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifan","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwei","family":"Zhai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nutrition and Metabolism, CAS Center for Excellence in Molecular Cell Sciences, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China"},{"name":"School of Life Science and Technology, Shanghai Tech University, Shanghai 200093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0303-7207(94)90076-0","article-title":"Protective action by hemin against interleukin-1-beta induced-inhibition of rat pancreatic-islet function","volume":"103","author":"Welsh","year":"1994","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.pharmthera.2005.10.017","article-title":"Heme as key regulator of major mammalian cellular functions: Molecular, cellular, and pharmacological aspects","volume":"111","author":"Tsiftsoglou","year":"2006","journal-title":"Pharmacol. Therapeut."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1182\/blood-2012-11-451229","article-title":"Hemolysis and free hemoglobin revisited: Exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins","volume":"121","author":"Schaer","year":"2013","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1093\/emboj\/20.11.2835","article-title":"Heme mediates derepression of maf recognition element through direct binding to transcription repressor bach1","volume":"20","author":"Ogawa","year":"2001","journal-title":"EMBO J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1073\/pnas.78.2.866","article-title":"Relationship between phosphorylation and activity of heme-regulated eukaryotic initiation-factor 2-alpha kinase","volume":"78","author":"Fagard","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1126\/science.1150179","article-title":"Rev-erb alpha, a heme sensor that coordinates metabolic and circadian pathways","volume":"318","author":"Yin","year":"2007","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1038\/nsmb1344","article-title":"Identification of heme as the ligand for the orphan nuclear receptors Rev-erb alpha and Rev-erb beta","volume":"14","author":"Raghuram","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.gene.2008.07.006","article-title":"Heme-binding to the nuclear receptor retinoid X receptor alpha (RXR alpha) leads to the inhibition of the transcriptional activity","volume":"423","author":"Gotoh","year":"2008","journal-title":"Gene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1210\/en.2009-0471","article-title":"Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats","volume":"151","author":"Ndisang","year":"2010","journal-title":"Endocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R211","DOI":"10.1152\/ajpregu.91000.2008","article-title":"The heme oxygenase system attenuates pancreatic lesions and improves insulin sensitivity and glucose metabolism in deoxycorticosterone acetate hypertension","volume":"298","author":"Ndisang","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E829","DOI":"10.1152\/ajpendo.90783.2008","article-title":"Heme oxygenase system enhances insulin sensitivity and glucose metabolism in streptozotocin-induced diabetes","volume":"296","author":"Ndisang","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1210\/en.2008-0239","article-title":"The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways","volume":"150","author":"Ndisang","year":"2009","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1210\/en.2008-1370","article-title":"Up-regulating the hemeoxygenase system enhances insulin sensitivity and improves glucose metabolism in insulin-resistant diabetes in Goto-Kakizaki rats","volume":"150","author":"Ndisang","year":"2009","journal-title":"Endocrinology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.biopha.2016.12.060","article-title":"Effects of the activation of heme oxygenase-1 on hormonal and metabolic changes in rats fed a high-fat diet","volume":"87","author":"Szkudelski","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1254\/jphs.14003FP","article-title":"Hemin improves insulin sensitivity in skeletal muscle in high fat-fed mice","volume":"126","author":"Ju","year":"2014","journal-title":"J. Pharmacol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1194\/jlr.M019257","article-title":"Liver patt1 deficiency protects male mice from age-associated but not high-fat diet-induced hepatic steatosis","volume":"53","author":"Liu","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20589","DOI":"10.1074\/jbc.M412357200","article-title":"Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes","volume":"280","author":"Frescas","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1111\/j.1365-2621.2002.tb08715.x","article-title":"Total heme and non-heme iron in raw and cooked meats","volume":"67","author":"Aguzzi","year":"2002","journal-title":"J. Food Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1042\/bj2440271","article-title":"Purification and properties of the soluble carnitine palmitoyltransferase from bovine liver-mitochondria","volume":"244","author":"Ramsay","year":"1987","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/0006-2952(95)02399-2","article-title":"Participation of a medium chain acyl-CoA synthetase in glycine conjugation of the benzoic acid derivatives with the electron-donating groups","volume":"51","author":"Kasuya","year":"1996","journal-title":"Biochem. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.cmet.2007.08.014","article-title":"Sirt1 improves insulin sensitivity under insulin-resistant conditions by repressing ptp1b","volume":"6","author":"Sun","year":"2007","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1073\/pnas.0630588100","article-title":"Triglyceride accumulation protects against fatty acid-induced lipotoxicity","volume":"100","author":"Listenberger","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.metabol.2015.07.006","article-title":"Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice","volume":"64","author":"Fu","year":"2015","journal-title":"Metabolism"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.4049\/jimmunol.176.7.4252","article-title":"Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction","volume":"176","author":"Devadas","year":"2006","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1002\/jcb.24061","article-title":"Heme induced oxidative stress attenuates sirtuin1 and enhances adipogenesis in mesenchymal stem cells and mouse pre-adipocytes","volume":"113","author":"Puri","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/0092-8674(81)90039-8","article-title":"Hemin enhances the differentiation of mouse 3T3 cells to adipocytes","volume":"26","author":"Chen","year":"1981","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1053\/j.gastro.2009.09.058","article-title":"Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice","volume":"138","author":"Yu","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"418","DOI":"10.3346\/jkms.2006.21.3.418","article-title":"A protective role for heme oxygenase-1 in INS-1 cells and rat islets that are exposed to high glucose conditions","volume":"21","author":"Won","year":"2006","journal-title":"J. Korean Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cell.2014.04.043","article-title":"Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man","volume":"158","author":"Jais","year":"2014","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"359732","DOI":"10.1155\/2010\/359732","article-title":"Role of heme oxygenase in inflammation, insulin-signalling, diabetes and obesity","volume":"2010","author":"Ndisang","year":"2010","journal-title":"Med. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22640","DOI":"10.1038\/srep22640","article-title":"Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1C protein stability","volume":"6","author":"Yan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/hep.24140","article-title":"Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation","volume":"53","author":"Herrero","year":"2011","journal-title":"Hepatology"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/9\/8\/805\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:07Z","timestamp":1760208247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/9\/8\/805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,26]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2017,8]]}},"alternative-id":["nu9080805"],"URL":"https:\/\/doi.org\/10.3390\/nu9080805","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,26]]}}}