{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T22:11:08Z","timestamp":1783548668588,"version":"3.55.0"},"reference-count":122,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01DK121797-01A1"],"award-info":[{"award-number":["1R01DK121797-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01DK126884-01"],"award-info":[{"award-number":["1R01DK126884-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K01HL-125445"],"award-info":[{"award-number":["K01HL-125445"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 HL05197-11"],"award-info":[{"award-number":["P01 HL05197-11"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM104357-02"],"award-info":[{"award-number":["P20GM104357-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heme oxygenase (HO) is a critical component of the defense mechanism to a wide variety of cellular stressors. HO induction affords cellular protection through the breakdown of toxic heme into metabolites, helping preserve cellular integrity. Nonalcoholic fatty liver disease (NAFLD) is a pathological condition by which the liver accumulates fat. The incidence of NAFLD has reached all-time high levels driven primarily by the obesity epidemic. NALFD can progress to nonalcoholic steatohepatitis (NASH), advancing further to liver cirrhosis or cancer. NAFLD is also a contributing factor to cardiovascular and metabolic diseases. There are currently no drugs to specifically treat NAFLD, with most treatments focused on lifestyle modifications. One emerging area for NAFLD treatment is the use of dietary supplements such as curcumin, pomegranate seed oil, milk thistle oil, cold-pressed Nigella Satvia oil, and resveratrol, among others. Recent studies have demonstrated that several of these natural dietary supplements attenuate hepatic lipid accumulation and fibrosis in NAFLD animal models. The beneficial actions of several of these compounds are associated with the induction of heme oxygenase-1 (HO-1). Thus, targeting HO-1 through dietary-supplements may be a useful therapeutic for NAFLD either alone or with lifestyle modifications.<\/jats:p>","DOI":"10.3390\/ijms21249493","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T21:25:08Z","timestamp":1607981108000},"page":"9493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-4008","authenticated-orcid":false,"given":"David E.","family":"Stec","sequence":"first","affiliation":[{"name":"Department of Physiology &amp; Biophysics, Center for Cardiovascular and Metabolic Diseases Research, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7599-1529","authenticated-orcid":false,"suffix":"Jr.","given":"Terry D.","family":"Hinds","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gtc.2019.09.007","article-title":"Burden of Disease due to Nonalcoholic Fatty Liver Disease","volume":"49","author":"Muthiah","year":"2020","journal-title":"Gastroenterol. Clin. North. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1016\/j.cgh.2019.12.026","article-title":"Nonalcoholic Fatty Liver Disease and Fibrosis Associated with Increased Risk of Cardiovascular Events in a Prospective Study","volume":"18","author":"Baratta","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement","volume":"73","author":"Eslam","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R207","DOI":"10.1152\/ajpregu.00517.2011","article-title":"Heme oxygenase, a novel target for the treatment of hypertension and obesity?","volume":"302","author":"Hosick","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Duvigneau, J.C., Esterbauer, H., and Kozlov, A.V. (2019). Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways. Antioxidants, 8.","DOI":"10.3390\/antiox8100475"},{"key":"ref_9","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-ERBalpha and REV-ERBbeta","volume":"14","author":"Raghuram","year":"2007","journal-title":"Nat. Struct Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/labinvest.3700691","article-title":"A novel endotoxin-induced pathway: Upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction","volume":"88","author":"Duvigneau","year":"2008","journal-title":"Lab. Invest."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1124\/pr.107.07104","article-title":"Pharmacological and clinical aspects of heme oxygenase","volume":"60","author":"Abraham","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2005.03.010","article-title":"Heme oxygenase and the cardiovascular-renal system","volume":"39","author":"Abraham","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1126\/science.2492116","article-title":"Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats","volume":"243","author":"Sacerdoti","year":"1989","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1172\/JCI114686","article-title":"Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats","volume":"86","author":"Levere","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1161\/01.HYP.38.2.210","article-title":"Human heme oxygenase-1 gene transfer lowers blood pressure and promotes growth in spontaneously hypertensive rats","volume":"38","author":"Sabaawy","year":"2001","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1161\/HYPERTENSIONAHA.108.114884","article-title":"Kidney-specific induction of heme oxygenase-1 prevents angiotensin II hypertension","volume":"52","author":"Vera","year":"2008","journal-title":"Hypertension"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1681\/ASN.2011050455","article-title":"Expression of heme oxygenase-1 in thick ascending loop of henle attenuates angiotensin II-dependent hypertension","volume":"23","author":"Stec","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1111\/j.1471-4159.1999.721187.x","article-title":"Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice","volume":"72","author":"Panahian","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1161\/hc3801.095663","article-title":"Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice","volume":"104","author":"Juan","year":"2001","journal-title":"Circulation"},{"key":"ref_20","unstructured":"Yachie, A., and Koizumi, S. (2001). Heme oxygenase 1 deficiency. Ryoikibetsu Shokogun Shirizu, 796\u2013797."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1053\/hupa.2002.30217","article-title":"Heme oxygenase-1 deficiency: The first autopsy case","volume":"33","author":"Kawashima","year":"2002","journal-title":"Hum. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/MPH.0b013e3181fd2aae","article-title":"Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia","volume":"33","author":"Radhakrishnan","year":"2011","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10919","DOI":"10.1073\/pnas.94.20.10919","article-title":"Heme oxygenase 1 is required for mammalian iron reutilization","volume":"94","author":"Poss","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/oby.20559","article-title":"Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21","volume":"22","author":"Hinds","year":"2014","journal-title":"Obesity (Silver Spring)"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1476-511X-10-31","article-title":"Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice","volume":"10","author":"Wang","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Salley, T.N., Mishra, M., Tiwari, S., Jadhav, A., and Ndisang, J.F. (2013). The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079270"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Raffaele, M., Carota, G., Sferrazzo, G., Licari, M., Barbagallo, I., Sorrenti, V., Signorelli, S.S., and Vanella, L. (2019). Inhibition of Heme Oxygenase Antioxidant Activity Exacerbates Hepatic Steatosis and Fibrosis In Vitro. Antioxidants, 8.","DOI":"10.3390\/antiox8080277"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5216","DOI":"10.1093\/emboj\/cdf516","article-title":"Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene","volume":"21","author":"Sun","year":"2002","journal-title":"EMBO J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/scrt176","article-title":"Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade","volume":"4","author":"Vanella","year":"2013","journal-title":"Stem Cell Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Monteiro, R., and Azevedo, I. (2010). Chronic inflammation in obesity and the metabolic syndrome. Mediat. Inflamm., 2010.","DOI":"10.1155\/2010\/289645"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Stec, D.E., John, K., Trabbic, C.J., Luniwal, A., Hankins, M.W., Baum, J., and Hinds, T.D. (2016). Bilirubin Binding to PPARalpha Inhibits Lipid Accumulation. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153427"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1161\/HYPERTENSIONAHA.118.11130","article-title":"Bilirubin, a Cardiometabolic Signaling Molecule","volume":"72","author":"Hinds","year":"2018","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9804","DOI":"10.1074\/jbc.RA120.013700","article-title":"Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor alpha","volume":"295","author":"Gordon","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Hinds, T.D., Creeden, J.F., Gordon, D.M., Stec, D.F., Donald, M.C., and Stec, D.E. (2020). Bilirubin nanoparticles reduce diet-induced hepatic steatosis, improve fat utilization, and increase plasma \u03b2-hydroxybutyrate. Front. Pharmacol.","DOI":"10.3389\/fphar.2020.594574"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1152\/physiolgenomics.00028.2019","article-title":"RNA-sequencing in human HepG2 hepatocytes reveals PPARalpha mediates transcriptome responsiveness of bilirubin","volume":"51","author":"Gordon","year":"2019","journal-title":"Physiol. Genom."},{"key":"ref_37","unstructured":"Creeden, J.F., Gordon, D.M., Stec, D.E., and Hinds, T.D. (2020). Bilirubin as a Metabolic Hormone: The Physiological Relevance of Low Levels. Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"G668","DOI":"10.1152\/ajpgi.00026.2018","article-title":"Biliverdin reductase and bilirubin in hepatic disease","volume":"314","author":"Weaver","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.cca.2011.04.013","article-title":"The role of oxidative stress in non-alcoholic steatohepatitis","volume":"412","author":"Koek","year":"2011","journal-title":"Clin. Chim. Acta."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.2174\/1389450116666150427155342","article-title":"Antioxidant Mechanisms in Nonalcoholic Fatty Liver Disease","volume":"16","author":"Liu","year":"2015","journal-title":"Curr. Drug Targets"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.tem.2018.01.002","article-title":"Bilirubin in the Liver-Gut Signaling Axis","volume":"29","author":"Hamoud","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.yexcr.2019.04.029","article-title":"Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1alpha-HO-1-PGC1alpha-mitochondrial signaling","volume":"380","author":"Raffaele","year":"2019","journal-title":"Exp. cell Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"R733","DOI":"10.1152\/ajpregu.00153.2019","article-title":"The loss of hepatic PPARalpha promotes inflammation and serum hyperlipidemia in diet-induced obesity","volume":"317","author":"Stec","year":"2019","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hinds, T.D., Creeden, J.F., Gordon, D.M., Spegele, A.C., Britton, S.L., Koch, L.G., and Stec, D.E. (2020). Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1. Antioxidants, 9.","DOI":"10.3390\/antiox9090889"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9125","DOI":"10.1074\/jbc.M209939200","article-title":"Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells","volume":"278","author":"Kitamuro","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22363","DOI":"10.1074\/jbc.M801784200","article-title":"BACH1 is a specific repressor of HMOX1 that is inactivated by arsenite","volume":"283","author":"Reichard","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"51769","DOI":"10.1074\/jbc.M409463200","article-title":"Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells: Insights from studies with small interfering RNAS","volume":"279","author":"Shan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3164\/jcbn.09-122GFR","article-title":"Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model","volume":"48","author":"Inoue","year":"2011","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.jnutbio.2013.12.011","article-title":"Characterization of docosahexaenoic acid (DHA)-induced heme oxygenase-1 (HO-1) expression in human cancer cells: The importance of enhanced BTB and CNC homology 1 (Bach1) degradation","volume":"25","author":"Wang","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.freeradbiomed.2009.11.007","article-title":"Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis","volume":"48","author":"Chowdhry","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"101412","DOI":"10.1016\/j.redox.2019.101412","article-title":"Hepatocyte-specific Nrf2 deficiency mitigates high-fat diet-induced hepatic steatosis: Involvement of reduced PPARgamma expression","volume":"30","author":"Li","year":"2020","journal-title":"Redox Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"E180","DOI":"10.1152\/ajpendo.00311.2017","article-title":"Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice","volume":"315","author":"Chartoumpekis","year":"2018","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104760","DOI":"10.1016\/j.phrs.2020.104760","article-title":"Obesity and NRF2-mediated cytoprotection: Where is the missing link?","volume":"156","author":"Vasileva","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Xu, L., Nagata, N., and Ota, T. (2019). Impact of Glucoraphanin-Mediated Activation of Nrf2 on Non-Alcoholic Fatty Liver Disease with a Focus on Mitochondrial Dysfunction. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20235920"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/ptr.6598","article-title":"Protective effects of glycycoumarin on liver diseases","volume":"34","author":"Zhang","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/13813450802033958","article-title":"Role of curcumin in health and disease","volume":"114","author":"Pari","year":"2008","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1139\/cjpp-2014-0174","article-title":"Effect of curcumin on hepatic heme oxygenase 1 expression in high fat diet fed rats: Is there a triangular relationship?","volume":"92","author":"Seyithanoglu","year":"2014","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/01.tp.0000184635.62570.13","article-title":"Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury","volume":"81","author":"McNally","year":"2006","journal-title":"Transplantation"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e13789","DOI":"10.14814\/phy2.13789","article-title":"Curcumin supplementation mitigates NASH development and progression in female Wistar rats","volume":"6","author":"Cunningham","year":"2018","journal-title":"Physiol. Rep."},{"key":"ref_60","first-page":"8234507","article-title":"PEGylated Curcumin Derivative Attenuates Hepatic Steatosis via CREB\/PPAR-gamma\/CD36 Pathway","volume":"2017","author":"Liu","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_61","first-page":"425","article-title":"Anti-Inflammatory Effects of Curcumin on Insulin Resistance Index, Levels of Interleukin-6, C-Reactive Protein, and Liver Histology in Polycystic Ovary Syndrome-Induced Rats","volume":"19","author":"Mohammadi","year":"2017","journal-title":"Cell J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.biopha.2018.05.135","article-title":"Curcumin regulates endogenous and exogenous metabolism via Nrf2-FXR-LXR pathway in NAFLD mice","volume":"105","author":"Yan","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Lee, D.E., Lee, S.J., Kim, S.J., Lee, H.S., and Kwon, O.S. (2019). Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Nutrients, 11.","DOI":"10.3390\/nu11112702"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"102283","DOI":"10.1016\/j.ctim.2019.102283","article-title":"The effects of curcumin supplementation on liver function, metabolic profile and body composition in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials","volume":"48","author":"Jalali","year":"2020","journal-title":"Complement. Ther. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/ptr.6542","article-title":"The effects of curcumin supplementation on body mass index, body weight, and waist circumference in patients with nonalcoholic fatty liver disease: A systematic review and dose-response meta-analysis of randomized controlled trials","volume":"34","author":"Baziar","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Saadati, S., Sadeghi, A., Mansour, A., Yari, Z., Poustchi, H., Hedayati, M., Hatami, B., and Hekmatdoost, A. (2019). Curcumin and inflammation in non-alcoholic fatty liver disease: A randomized, placebo controlled clinical trial. BMC Gastroenterol., 19.","DOI":"10.1186\/s12876-019-1055-4"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"102447","DOI":"10.1016\/j.ctim.2020.102447","article-title":"A pilot study of the effect of curcumin on epigenetic changes and DNA damage among patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, clinical trial","volume":"51","author":"Hariri","year":"2020","journal-title":"Complement. Ther. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1017\/S0007114519002484","article-title":"Randomised trial of chronic supplementation with a nutraceutical mixture in subjects with non-alcoholic fatty liver disease","volume":"123","author":"Cerletti","year":"2020","journal-title":"Br. J. Nutr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0378-8741(98)00222-0","article-title":"Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids","volume":"66","author":"Schubert","year":"1999","journal-title":"J. Ethnopharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"163","DOI":"10.5740\/jaoacint.11-178","article-title":"Composition of pomegranate juice","volume":"95","author":"Krueger","year":"2012","journal-title":"J. AOAC Int."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Sodhi, K., Puri, N., Favero, G., Stevens, S., Meadows, C., Abraham, N.G., Rezzani, R., Ansinelli, H., Lebovics, E., and Shapiro, J.I. (2015). Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0128648"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1159\/000330116","article-title":"Effect of pomegranate juice on insulin secretion and sensitivity in patients with obesity","volume":"58","year":"2011","journal-title":"Ann. Nutr. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1017\/S0007114508159001","article-title":"Pomegranate seed oil consumption during a period of high-fat feeding reduces weight gain and reduces type 2 diabetes risk in CD-1 mice","volume":"102","author":"McFarlin","year":"2009","journal-title":"Br. J. Nutr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.fct.2011.03.037","article-title":"Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice","volume":"49","author":"Vroegrijk","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1463-1326.2009.01132.x","article-title":"The effects of Xanthigen in the weight management of obese premenopausal women with non-alcoholic fatty liver disease and normal liver fat","volume":"12","author":"Abidov","year":"2010","journal-title":"Diabetes Obes. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Raffaele, M., Licari, M., Amin, S., Alex, R., Shen, H.H., Singh, S.P., Vanella, L., Rezzani, R., Bonomini, F., and Peterson, S.J. (2020). Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155469"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1089\/ars.2019.7989","article-title":"The PGC-1alpha -HO-1 axis, a powerful antioxidative pathway with potential to attenuate diabetic cardiomyopathy","volume":"32","author":"Waldman","year":"2020","journal-title":"Antioxid. Redox Signal."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Meddeb, W., Rezig, L., Abderrabba, M., Lizard, G., and Mejri, M. (2017). Tunisian Milk Thistle: An Investigation of the Chemical Composition and the Characterization of Its Cold-Pressed Seed Oils. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122582"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.2174\/0929867324666170616110748","article-title":"Effects of Polyphenolic Derivatives on Heme Oxygenase-System in Metabolic Dysfunctions","volume":"25","author":"Pittala","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_80","first-page":"1073","article-title":"Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD)","volume":"8","author":"Ni","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1089\/jmf.2013.0179","article-title":"Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl(4)-treated rats","volume":"18","author":"Clichici","year":"2015","journal-title":"J. Med. Food"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s40268-014-0068-2","article-title":"In vivo efficacy study of milk thistle extract (ETHIS-094) in STAM model of nonalcoholic steatohepatitis","volume":"14","author":"Pais","year":"2014","journal-title":"Drugs R&D"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6026902","DOI":"10.1155\/2019\/6026902","article-title":"Isolated Silymarin Flavonoids Increase Systemic and Hepatic Bilirubin Concentrations and Lower Lipoperoxidation in Mice","volume":"2019","author":"Suk","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"E244","DOI":"10.1152\/ajpendo.00396.2016","article-title":"Mice with hyperbilirubinemia due to Gilbert\u2019s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha","volume":"312","author":"Hinds","year":"2017","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"25179","DOI":"10.1074\/jbc.M116.731703","article-title":"Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha","volume":"291","author":"Hinds","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3350\/cmh.2012.18.4.383","article-title":"Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease","volume":"18","author":"Kwak","year":"2012","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1111\/j.1365-2036.2012.05114.x","article-title":"Unconjugated hyperbilirubinemia is inversely associated with non-alcoholic steatohepatitis (NASH)","volume":"35","author":"Hjelkrem","year":"2012","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/MPG.0b013e318291fefe","article-title":"Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children","volume":"57","author":"Puri","year":"2013","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.mehy.2016.08.013","article-title":"Does bilirubin prevent hepatic steatosis through activation of the PPARalpha nuclear receptor?","volume":"95","author":"Hinds","year":"2016","journal-title":"Med. Hypotheses"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Shen, H.H., Alex, R., Bellner, L., Raffaele, M., Licari, M., Vanella, L., Stec, D.E., and Abraham, N.G. (2020). Milk thistle seed cold press oil attenuates markers of the metabolic syndrome in a mouse model of dietary-induced obesity. J. Food Biochem., e13522.","DOI":"10.1111\/jfbc.13522"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/clpt.2009.311","article-title":"Obesity, inflammation, and cardiovascular risk","volume":"87","author":"Mathieu","year":"2010","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s12011-014-0114-5","article-title":"Nigella sativa oil reduces aluminium chloride-induced oxidative injury in liver and erythrocytes of rats","volume":"162","author":"Bouasla","year":"2014","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1142\/S0192415X03001399","article-title":"Protective effect of Nigella sativa seeds against carbon tetrachloride-induced liver damage","volume":"31","year":"2003","journal-title":"Am. J. Chin. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.biopha.2018.12.037","article-title":"Protective effects of Nigella sativa oil against carboplatin-induced liver damage in rats","volume":"110","author":"Erisgin","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1080\/01902148.2020.1801895","article-title":"Thymoquinone ameliorates the PM2.5-induced lung injury in rats","volume":"46","author":"Mao","year":"2020","journal-title":"Exp. Lung Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"751","DOI":"10.6061\/clinics\/2015(11)07","article-title":"Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats","volume":"70","author":"Jaarin","year":"2015","journal-title":"Clinics (Sao Paulo)"},{"key":"ref_97","unstructured":"Licari, M., Raffaele, M., Rosman, Z.F., Schragenheim, J., Bellner, L., Vanella, L., Rezzani, R., Rodella, L., Bonomini, F., and Hochhauser, E. (2019). Abraham NG. Beneficial Effects of Thymoquinone on Metabolic Function and Fatty Liver in a Murine Model of Obesity. J. Nutr. Food Sci., 9."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Shen, H.H., Peterson, S.J., Bellner, L., Choudhary, A., Levy, L., Gancz, L., Sasson, A., Trainer, J., Rezzani, R., and Resnick, A. (2020). Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice. Antioxidants, 9.","DOI":"10.3390\/antiox9060489"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.fct.2013.12.015","article-title":"Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2\/ARE activation: Akt and AMPKalpha as upstream targets","volume":"65","author":"Kundu","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s40200-019-00439-6","article-title":"The effect of Nigella sativa oil on serum levels of inflammatory markers, liver enzymes, lipid profile, insulin and fasting blood sugar in patients with non-alcoholic fatty liver","volume":"18","author":"Rashidmayvan","year":"2019","journal-title":"J. Diabetes Metab. Disord."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/j.1749-6632.2003.tb07534.x","article-title":"Potential mechanism by which resveratrol, a red wine constituent, protects neurons","volume":"993","author":"Zhuang","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.expneurol.2010.03.032","article-title":"Resveratrol protects against experimental stroke: Putative neuroprotective role of heme oxygenase 1","volume":"224","author":"Sakata","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.freeradbiomed.2007.05.004","article-title":"Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase","volume":"43","author":"Thirunavukkarasu","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1080\/10715760600833085","article-title":"Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB","volume":"40","author":"Das","year":"2006","journal-title":"Free Radic. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"9180","DOI":"10.1021\/jf302831d","article-title":"Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells","volume":"60","author":"Cheng","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.bbrc.2005.03.237","article-title":"Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells","volume":"331","author":"Chen","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"105667","DOI":"10.1016\/j.biocel.2019.105667","article-title":"Resveratrol alleviates non-alcoholic fatty liver disease through epigenetic modification of the Nrf2 signaling pathway","volume":"119","author":"Hosseini","year":"2020","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1017\/S0007114511002753","article-title":"Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress","volume":"107","author":"Macarulla","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Bujanda, L., Hijona, E., Larzabal, M., Beraza, M., Aldazabal, P., Garcia-Urkia, N., Sarasqueta, C., Cosme, A., Irastorza, B., and Gonzalez, A. (2008). Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol., 8.","DOI":"10.1186\/1471-230X-8-40"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.bbrc.2009.01.163","article-title":"Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway","volume":"380","author":"Wang","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"504","DOI":"10.18433\/jpps29994","article-title":"Resveratrol Limits Lipogenesis and Enhance Mitochondrial Activity in HepG2 Cells","volume":"21","author":"Izdebska","year":"2018","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jconrel.2019.06.023","article-title":"The hepatic-targeted, resveratrol loaded nanoparticles for relief of high fat diet-induced nonalcoholic fatty liver disease","volume":"307","author":"Teng","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.biopha.2018.11.088","article-title":"A novel resveratrol-curcumin hybrid, a19, attenuates high fat diet-induced nonalcoholic fatty liver disease","volume":"110","author":"Wu","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1080\/13813455.2018.1441872","article-title":"Effects of combined therapy with resveratrol, continuous and interval exercises on apoptosis, oxidative stress, and inflammatory biomarkers in the liver of old rats with non-alcoholic fatty liver disease","volume":"125","author":"Hajighasem","year":"2019","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3109\/00365521.2015.1107620","article-title":"Placebo-controlled, randomised clinical trial: High-dose resveratrol treatment for non-alcoholic fatty liver disease","volume":"51","author":"Heeboll","year":"2016","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1016\/j.cgh.2014.02.024","article-title":"Resveratrol does not benefit patients with nonalcoholic fatty liver disease","volume":"12","author":"Chachay","year":"2014","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1111\/dom.13268","article-title":"Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: A randomized, double-blind, placebo-controlled clinical trial","volume":"20","author":"Kantartzis","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1024\/0300-9831\/a000528","article-title":"No beneficial effects of resveratrol supplementation on atherogenic risk factors in patients with nonalcoholic fatty liver disease","volume":"90","author":"Farzin","year":"2020","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"59","DOI":"10.15403\/jgld.2014.1121.261.ely","article-title":"Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis","volume":"26","author":"Elgebaly","year":"2017","journal-title":"J. Gastrointestin. Liver Dis."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Jakubczyk, K., Skonieczna-Zydecka, K., Kaldunska, J., Stachowska, E., Gutowska, I., and Janda, K. (2020). Effects of Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease-A Meta-Analysis. Nutrients, 12.","DOI":"10.3390\/nu12082435"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1091\/mbc.e08-10-1005","article-title":"Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants","volume":"20","author":"Weis","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Zhang, M., Nakamura, K., Kageyama, S., Lawal, A.O., Gong, K.W., Bhetraratana, M., Fujii, T., Sulaiman, D., Hirao, H., and Bolisetty, S. (2018). Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury. JCI Insight, 3.","DOI":"10.1172\/jci.insight.120596"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9493\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:44:44Z","timestamp":1760179484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/24\/9493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,14]]},"references-count":122,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21249493"],"URL":"https:\/\/doi.org\/10.3390\/ijms21249493","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,14]]}}}