{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:01:01Z","timestamp":1782482461814,"version":"3.54.5"},"reference-count":68,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T00:00:00Z","timestamp":1596153600000},"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":["Health  R 56-139561,1R01 DK121748-01A1, P01 HL05197-11"],"award-info":[{"award-number":["Health  R 56-139561,1R01 DK121748-01A1, P01 HL05197-11"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM104357-02"],"award-info":[{"award-number":["P20GM104357-02"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. Method: In this in vivo study, eight-week-old C57BL\/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL\/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p &lt; 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1\u03b1. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-972, p-IRB tyr1146, and pAMPK, thereby decreasing insulin resistance. Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.<\/jats:p>","DOI":"10.3390\/ijms21155469","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T04:15:31Z","timestamp":1596168931000},"page":"5469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice"],"prefix":"10.3390","volume":"21","author":[{"given":"Marco","family":"Raffaele","sequence":"first","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"},{"name":"Department of Drug Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Licari","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"},{"name":"Department of Drug Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif","family":"Amin","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragin","family":"Alex","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-hsueh","family":"Shen","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2996-0374","authenticated-orcid":false,"given":"Shailendra P.","family":"Singh","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"},{"name":"Departments of Biotechnology and Biomedical Engineering, Central University of Rajasthan, Rajasthan 305817, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6314-6029","authenticated-orcid":false,"given":"Luca","family":"Vanella","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7515-5846","authenticated-orcid":false,"given":"Rita","family":"Rezzani","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-0308","authenticated-orcid":false,"given":"Francesca","family":"Bonomini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6847-3969","authenticated-orcid":false,"given":"Stephen J.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Medicine, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-4008","authenticated-orcid":false,"given":"David E.","family":"Stec","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-1959","authenticated-orcid":false,"given":"Nader G.","family":"Abraham","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA"},{"name":"Department of Drug Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1089\/lap.2018.0380","article-title":"Epidemiology of Obesity and Associated Comorbidities","volume":"28","author":"Andolfi","year":"2018","journal-title":"J. Laparoendosc. Adv. Surg. Tech. A"},{"key":"ref_2","first-page":"124","article-title":"Obesity and hypertension, heart failure, and coronary heart disease-risk factor, paradox, and recommendations for weight loss","volume":"9","author":"Artham","year":"2009","journal-title":"Ochsner J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Singh, S.P., Greenberg, M., Glick, Y., Bellner, L., Favero, G., Rezzani, R., Rodella, L.F., Agostinucci, K., Shapiro, J.I., and Abraham, N.G. (2020). Adipocyte Specific HO-1 Gene Therapy is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model. Antioxidants (Basel), 9.","DOI":"10.3390\/antiox9010040"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1053\/jhep.2003.50161","article-title":"Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome","volume":"37","author":"Marchesini","year":"2003","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.3748\/wjg.v13.i26.3540","article-title":"Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease","volume":"13","author":"Qureshi","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"108073","DOI":"10.1016\/j.abb.2019.108073","article-title":"HO-1 Overexpression and Underexpression: Clinical Implications","volume":"673","author":"Drummond","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.3390\/ijms12053117","article-title":"Inflammation, oxidative stress, and obesity","volume":"12","author":"Bautista","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_8","first-page":"193","article-title":"Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease","volume":"70","author":"Holvoet","year":"2008","journal-title":"Verh. K. Acad. Geneeskd. Belg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/oby.22608","article-title":"Cardioprotective heme oxygenase-1-PGC-1\u03b1 signaling in epicardial fat attenuates cardiovascular risk in humans as in obese mice","volume":"27","author":"Singh","year":"2019","journal-title":"Obesity (Silver Spring)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.tips.2015.09.003","article-title":"Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome","volume":"37","author":"Abraham","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"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":"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_13","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.2174\/1381612033453758","article-title":"Therapeutic applications of human heme oxygenase gene transfer and gene therapy","volume":"9","author":"Abraham","year":"2003","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"412","DOI":"10.2174\/138161208783597371","article-title":"Heme oxygenase: A target gene for anti-diabetic and obesity","volume":"14","author":"Abraham","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.2337\/db15-0617","article-title":"NOV\/CCN3: A New Adipocytokine Involved in Obesity-Associated Insulin Resistance","volume":"65","author":"Martinerie","year":"2016","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"H368","DOI":"10.1152\/ajpheart.00093.2017","article-title":"EET Intervention on Wnt1, NOV and HO-1 Signaling Prevents Obesity-Induced Cardiomyopathy in Obese Mice","volume":"313","author":"Cao","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neuron.2017.09.056","article-title":"Cell Biology of Astrocyte-Synapse Interactions","volume":"96","author":"Allen","year":"2017","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.cellsig.2007.01.020","article-title":"TNF-alpha-induced NF-kappaB\/RelA Ser(276) phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway","volume":"19","author":"Jamaluddin","year":"2007","journal-title":"Cell Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2009.07.031","article-title":"Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome","volume":"314","author":"Maury","year":"2010","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1002\/oby.22354","article-title":"Oxidized HDL, Adipokines, and Endothelial Dysfunction: A Potential Biomarker Profile for Cardiovascular Risk in Women with Obesity","volume":"27","author":"Peterson","year":"2019","journal-title":"Obesity (Silver Spring)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1161\/hh1201.092042","article-title":"Diabetes mellitus enhances vascular matrix metalloproteinase activity: Role of oxidative stress","volume":"88","author":"Uemura","year":"2001","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1681\/ASN.2013010069","article-title":"Endothelial Sirtuin 1 Deficiency Perpetrates Nephrosclerosis through Downregulation of Matrix Metalloproteinase-14: Relevance to Fibrosis of Vascular Senescence","volume":"25","author":"Vasko","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.bbrc.2012.11.071","article-title":"p38 MAPK alpha mediates cytokine-induced IL-6 and MMP-3 expression in human cardiac fibroblasts","volume":"430","author":"Sinfield","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/hep.510300236","article-title":"MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells","volume":"30","author":"Theret","year":"1999","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"639541","DOI":"10.1155\/2013\/639541","article-title":"Therapeutic roles of heme oxygenase-1 in metabolic diseases: Curcumin and resveratrol analogues as possible inducers of heme oxygenase-1","volume":"2013","author":"Son","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E645","DOI":"10.1152\/ajpendo.00111.2007","article-title":"Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase\/Akt-mediated pathway in mouse beta-cells","volume":"293","author":"Pugazhenthi","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1016\/j.lfs.2007.02.002","article-title":"Phosphatidylinositol-3-kinase is involved in the antihyperglycemic effect induced by resveratrol in streptozotocin-induced diabetic rats","volume":"80","author":"Chi","year":"2007","journal-title":"Life Sci."},{"key":"ref_28","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 (Basel), 9.","DOI":"10.3390\/antiox9060489"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"918209","DOI":"10.1155\/2014\/918209","article-title":"Composition, in vitro antioxidant and antimicrobial activities of essential oil and oleoresins obtained from black cumin seeds (Nigella sativa L.)","volume":"2014","author":"Singh","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15166","DOI":"10.1074\/jbc.275.20.15166","article-title":"A mammalian iron ATPase induced by iron","volume":"275","author":"Baranano","year":"2000","journal-title":"J. Biol. Chem"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e0013","DOI":"10.5041\/RMMJ.10113","article-title":"Pomegranate for your cardiovascular health","volume":"4","author":"Aviram","year":"2013","journal-title":"Rambam Maimonides Med. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"544","DOI":"10.3389\/fphar.2018.00544","article-title":"Vasculoprotective Effects of Pomegranate (Punica granatum L.)","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_33","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_34","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_35","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_36","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_37","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s11130-017-0605-6","article-title":"Effects of Pomegranate Juice on Cardiovascular Risk Factors in Patients with Metabolic Syndrome: A Double-Blinded, Randomized Crossover Controlled Trial","volume":"72","author":"Moazzen","year":"2017","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1093\/aje\/kws448","article-title":"Prevalence of nonalcoholic fatty liver disease in the United States: The Third National Health and Nutrition Examination Survey, 1988\u20131994","volume":"178","author":"Lazo","year":"2013","journal-title":"Am. J. Epidemiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/j.1365-2036.2011.04724.x","article-title":"Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults","volume":"34","author":"Vernon","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1111\/dom.12973","article-title":"Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes","volume":"19","author":"Cusi","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_41","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_42","first-page":"S39","article-title":"Weight loss as a treatment for nonalcoholic fatty liver disease","volume":"40","author":"Clark","year":"2006","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.2174\/1381612826666200204095401","article-title":"Lifestyle changes for the treatment of nonalcoholic fatty liver disease\u2014A 2015-19 update","volume":"26","author":"Petroni","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Reginato, E., Pippi, R., Aiello, C., Sbroma Tomaro, E., Ranucci, C., Buratta, L., Bini, V., Marchesini, G., De Feo, P., and Fanelli, C. (2019). Effect of Short Term Intensive Lifestyle Intervention on Hepatic Steatosis Indexes in Adults with Obesity and\/or Type 2 Diabetes. J. Clin. Med., 8.","DOI":"10.3390\/jcm8060851"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Singh, S., Grant, I., Meissner, A., Kappas, A., and Abraham, N. (2017). Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1alpha in female mice. Horm. Mol. Biol. Clin. Investig., 31.","DOI":"10.1515\/hmbci-2017-0027"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16082","DOI":"10.1038\/s41598-017-16463-6","article-title":"Increased inflammation, oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice","volume":"7","author":"Alcala","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.freeradbiomed.2013.08.174","article-title":"Free radical biology for medicine: Learning from nonalcoholic fatty liver disease","volume":"65","author":"Serviddio","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3484107","DOI":"10.1155\/2018\/3484107","article-title":"Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress","volume":"2018","author":"Sacerdoti","year":"2018","journal-title":"Int. J. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1089\/ars.2016.6776","article-title":"Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis","volume":"26","author":"Spahis","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9635","DOI":"10.1073\/pnas.1207287109","article-title":"Development of insulin resistance in mice lacking PGC-1alpha in adipose tissues","volume":"109","author":"Kleiner","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.prostaglandins.2016.07.004","article-title":"PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid","volume":"125","author":"Singh","year":"2016","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"43112","DOI":"10.1074\/jbc.M111.252775","article-title":"Peroxisome proliferator-activated receptor alpha (PPARalpha) induces PPARgamma coactivator 1alpha (PGC-1alpha) gene expression and contributes to thermogenic activation of brown fat: Involvement of PRDM16","volume":"286","author":"Hondares","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1750-1326-8-32","article-title":"Dominant optic atrophy, OPA1, and mitochondrial quality control: Understanding mitochondrial network dynamics","volume":"8","author":"Alavi","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.cell.2006.06.010","article-title":"Mitochondria: Dynamic organelles in disease, aging, and development","volume":"125","author":"Chan","year":"2006","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5523","DOI":"10.1073\/pnas.1108220109","article-title":"Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis","volume":"109","author":"Sebastian","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.prostaglandins.2018.05.008","article-title":"EET enhances renal function in obese mice resulting in restoration of HO-1-Mfn1\/2 signaling, and decrease in hypertension through inhibition of sodium chloride co-transporter","volume":"137","author":"Schragenheim","year":"2018","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Fakhouri, E.W., Peterson, S.J., Kothari, J., Alex, R., Shapiro, J.I., and Abraham, N.G. (2020). Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm. Antioxidants (Basel), 9.","DOI":"10.3390\/antiox9070636"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1161\/HYPERTENSIONAHA.112.193805","article-title":"Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet","volume":"60","author":"Cao","year":"2012","journal-title":"Hypertension"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1161\/HYPERTENSIONAHA.110.151423","article-title":"Adipocyte heme oxygenase-1 induction attenuates metabolic syndrome in both male and female obese mice","volume":"56","author":"Burgess","year":"2010","journal-title":"Hypertension"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/ijo.2011.78","article-title":"Chronic HO-1 induction with cobalt protoporphyrin (CoPP) treatment increases oxygen consumption, activity, heat production and lowers body weight in obese melanocortin-4 receptor-deficient mice","volume":"36","author":"Csongradi","year":"2012","journal-title":"Int. J. Obes. (Lond.)"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.bone.2009.10.012","article-title":"HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage","volume":"46","author":"Vanella","year":"2010","journal-title":"Bone"},{"key":"ref_62","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_63","doi-asserted-by":"crossref","unstructured":"Lakhani, H.V., Zehra, M., Pillai, S.S., Puri, N., Shapiro, J.I., Abraham, N.G., and Sodhi, K. (2019). Beneficial Role of HO-1-SIRT1 Axis in Attenuating Angiotensin II-Induced Adipocyte Dysfunction. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133205"},{"key":"ref_64","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_65","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.7150\/ijbs.27173","article-title":"The PI3K\/AKT pathway in obesity and type 2 diabetes","volume":"14","author":"Huang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"107092","DOI":"10.1016\/j.diabres.2017.10.004","article-title":"Akt activation: A potential strategy to ameliorate insulin resistance","volume":"156","author":"Zhang","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_67","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_68","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1124\/jpet.103.057315","article-title":"Role of the heme oxygenases in abnormalities of the mesenteric circulation in cirrhotic rats","volume":"308","author":"Sacerdoti","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5469\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:53:11Z","timestamp":1760176391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5469"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,31]]},"references-count":68,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21155469"],"URL":"https:\/\/doi.org\/10.3390\/ijms21155469","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,31]]}}}