{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:41:40Z","timestamp":1779230500955,"version":"3.51.4"},"reference-count":86,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T00:00:00Z","timestamp":1624752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["PROGRES Q40\/O2"],"award-info":[{"award-number":["PROGRES Q40\/O2"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education, Youth and Sports of the Czech Republic and European Union","award":["CZ.02.1.01\/0.0\/0.0\/18_069\/0010046"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/18_069\/0010046"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL\/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC\/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.<\/jats:p>","DOI":"10.3390\/ijms22136908","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T22:24:57Z","timestamp":1624832697000},"page":"6908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9823-542X","authenticated-orcid":false,"given":"Pavla","family":"Sta\u0148kov\u00e1","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5251-5343","authenticated-orcid":false,"given":"Otto","family":"Ku\u010dera","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Peterov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"},{"name":"Department of Medical Biochemistry, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moustafa","family":"Elkalaf","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"},{"name":"Department of Pathophysiology, Third Faculty of Medicine, Charles University Prague, Rusk\u00e1 87, 100 00 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Rychtrmoc","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-1116","authenticated-orcid":false,"given":"Jan","family":"Melek","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miroslav","family":"Podhola","sequence":"additional","affiliation":[{"name":"The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9 and University Hospital Hradec Kr\u00e1lov\u00e9, Sokolsk\u00e1 581, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronika","family":"Zub\u00e1\u0148ov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"},{"name":"Department of Clinical Biochemistry and Diagnostics, Charles University, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9 and University Hospital Hradec Kr\u00e1lov\u00e9, Sokolsk\u00e1 581, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3908-290X","authenticated-orcid":false,"given":"Zuzana","family":"\u010cervinkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine in Hradec Kr\u00e1lov\u00e9, Charles University, \u0160imkova 870, 500 03 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-3-319-48382-5_7","article-title":"Adipose Tissue Function and Expandability as Determinants of Lipotoxicity and the Metabolic Syndrome","volume":"960","author":"Carobbio","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/er.2017-00211","article-title":"Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease","volume":"39","author":"Smith","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102336","DOI":"10.1016\/j.ceca.2020.102336","article-title":"Role of mitochondria in liver metabolic health and diseases","volume":"94","author":"Morio","year":"2021","journal-title":"Cell Calcium"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.metabol.2018.09.005","article-title":"The epidemiology of obesity","volume":"92","author":"Chooi","year":"2019","journal-title":"Metabolism"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/joim.12803","article-title":"Inflammation of brown\/beige adipose tissues in obesity and metabolic disease","volume":"284","author":"Villarroya","year":"2018","journal-title":"J. Intern. Med."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4254\/wjh.v9.i11.533","article-title":"Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management","volume":"9","author":"Cholankeril","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1177\/1479164119827611","article-title":"Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift","volume":"16","author":"Nolan","year":"2019","journal-title":"Diab. Vasc. Dis. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8713","DOI":"10.3390\/ijms15058713","article-title":"Role of mitochondria in nonalcoholic fatty liver disease","volume":"15","author":"Nassir","year":"2014","journal-title":"Int. J. Mol. Sci"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1007\/s00018-018-2860-6","article-title":"Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease","volume":"75","author":"Ipsen","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.tem.2016.11.006","article-title":"Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies","volume":"28","author":"Sunny","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"G825","DOI":"10.1152\/ajpgi.00145.2011","article-title":"Fast food diet mouse: Novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition","volume":"301","author":"Charlton","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E418","DOI":"10.1152\/ajpendo.00319.2015","article-title":"Metabolic phenotype and adipose and liver features in a high-fat Western diet-induced mouse model of obesity-linked NAFLD","volume":"310","author":"Luo","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Stankova, P., Kucera, O., Peterova, E., Lotkova, H., Maseko, T.E., Nozickova, K., and Cervinkova, Z. (2020). Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031101"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.bbabio.2016.03.012","article-title":"Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis","volume":"1857","author":"Tretter","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.tibs.2017.01.003","article-title":"Mitochondrial Complex II: At the Crossroads","volume":"42","author":"Rohlena","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.2337\/db14-0346","article-title":"Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity","volume":"64","author":"McCreath","year":"2015","journal-title":"Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/MCG.0b013e3181dd1348","article-title":"Generalizability of the nonalcoholic steatohepatitis Clinical Research Network histologic scoring system for nonalcoholic fatty liver disease","volume":"45","author":"Juluri","year":"2011","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1365-2036.2011.04695.x","article-title":"Validation of the non-alcoholic fatty liver disease activity score","volume":"34","author":"Hjelkrem","year":"2011","journal-title":"Aliment. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e01231","DOI":"10.1016\/j.heliyon.2019.e01231","article-title":"Histological and biochemical evaluation of transforming growth factor-\u03b2 activation and its clinical significance in patients with chronic liver disease","volume":"5","author":"Yokoyama","year":"2019","journal-title":"Heliyon"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Batra, J., Robinson, J., Mehner, C., Hockla, A., Miller, E., Radisky, D.C., and Radisky, E.S. (2012). PEGylation extends circulation half-life while preserving in vitro and in vivo activity of tissue inhibitor of metalloproteinases-1 (TIMP-1). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050028"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/his.13665","article-title":"Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease","volume":"73","author":"Munsterman","year":"2018","journal-title":"Histopathology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"C1034","DOI":"10.1152\/ajpcell.00175.2012","article-title":"Pannexin1 contributes to pathophysiological ATP release in lipoapoptosis induced by saturated free fatty acids in liver cells","volume":"303","author":"Xiao","year":"2012","journal-title":"Am. J. Physiol Cell Physiol."},{"key":"ref_24","unstructured":"Gnaiger, E. (2020). and MitoEAGLE Task Group (2020). Mitochondrial physiology. Bioenerg. Commun., 20."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"Chandel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.mito.2010.03.001","article-title":"Succinate dehydrogenase\u2014Assembly, regulation and role in human disease","volume":"10","author":"Rutter","year":"2010","journal-title":"Mitochondrion"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Meyer, J.G., Softic, S., Basisty, N., Rardin, M.J., Verdin, E., Gibson, B.W., Ilkayeva, O., Newgard, C.B., Kahn, C.R., and Schilling, B. (2018). Temporal dynamics of liver mitochondrial protein acetylation and succinylation and metabolites due to high fat diet and\/or excess glucose or fructose. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0208973"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3389\/fendo.2018.00455","article-title":"Succinate as a Regulator of Hepatic Stellate Cells in Liver Fibrosis","volume":"9","author":"Cho","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10277","DOI":"10.1074\/jbc.M115.692244","article-title":"Sirtuin 3 (SIRT3) Regulates alpha-Smooth Muscle Actin (alpha-SMA) Production through the Succinate Dehydrogenase-G Protein-coupled Receptor 91 (GPR91) Pathway in Hepatic Stellate Cells","volume":"291","author":"Li","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"80","DOI":"10.15280\/jlm.2014.4.2.80","article-title":"SIRT3 as a Regulator of Non-alcoholic Fatty Liver Disease","volume":"4","author":"Cho","year":"2014","journal-title":"J. Lifestyle Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3389\/fonc.2017.00058","article-title":"The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells","volume":"7","author":"Masgras","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s12192-016-0687-3","article-title":"Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells","volume":"21","author":"Im","year":"2016","journal-title":"Cell Stress Chaperones"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1074\/mcp.M113.028027","article-title":"Proteomic differences between hepatocellular carcinoma and nontumorous liver tissue investigated by a combined gel-based and label-free quantitative proteomics study","volume":"12","author":"Megger","year":"2013","journal-title":"Mol. Cell Proteom."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11897","DOI":"10.18632\/oncotarget.2472","article-title":"Inhibition of succinate dehydrogenase by the mitochondrial chaperone TRAP1 has anti-oxidant and anti-apoptotic effects on tumor cells","volume":"5","author":"Guzzo","year":"2014","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1074\/jbc.M115.656934","article-title":"Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria","volume":"291","author":"Kim","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_36","first-page":"2681","article-title":"Downregulation of TRAP1 aggravates injury of H9c2 cardiomyocytes in a hyperglycemic state","volume":"18","author":"Zhang","year":"2019","journal-title":"Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1080\/13510002.2020.1752002","article-title":"Mitochondrial complex II and reactive oxygen species in disease and therapy","volume":"25","author":"Kraus","year":"2020","journal-title":"Redox Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3109\/10409238.2014.990556","article-title":"Protein-mediated assembly of succinate dehydrogenase and its cofactors","volume":"50","author":"Na","year":"2015","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1007\/s00018-019-03200-7","article-title":"The assembly of succinate dehydrogenase: A key enzyme in bioenergetics","volume":"76","author":"Moosavi","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0014-5793(00)01322-3","article-title":"The chaperonin-related protein Tcm62p ensures mitochondrial gene expression under heat stress","volume":"470","author":"Klanner","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s00285-018-1248-4","article-title":"Limits of noise for autoregulated gene expression","volume":"77","author":"Czuppon","year":"2018","journal-title":"J. Math. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1007\/s11095-011-0566-7","article-title":"Inhibitors of succinate: Quinone reductase\/Complex II regulate production of mitochondrial reactive oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death","volume":"28","author":"Ralph","year":"2011","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E374","DOI":"10.1152\/ajpendo.00088.2019","article-title":"Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints","volume":"317","author":"Kappler","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Moreno, C., Santos, R.M., Burns, R., and Zhang, W.C. (2020). Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases. Cancers, 12.","DOI":"10.3390\/cancers12113237"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27255","DOI":"10.1074\/jbc.M112.374629","article-title":"Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions","volume":"287","author":"Quinlan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.bbabio.2013.01.004","article-title":"Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning","volume":"1827","author":"Drose","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.cell.2014.11.034","article-title":"Metabolic inflexibility: When mitochondrial indecision leads to metabolic gridlock","volume":"159","author":"Muoio","year":"2014","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1002\/hep4.1271","article-title":"Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease","volume":"2","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.lfs.2007.04.023","article-title":"Antioxidant properties of Krebs cycle intermediates against malonate pro-oxidant activity in vitro: A comparative study using the colorimetric method and HPLC analysis to determine malondialdehyde in rat brain homogenates","volume":"81","author":"Puntel","year":"2007","journal-title":"Life Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.mito.2017.03.005","article-title":"Uncoupling protein 2 and metabolic diseases","volume":"34","author":"Sreedhar","year":"2017","journal-title":"Mitochondrion"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.tibs.2009.11.001","article-title":"The on-off switches of the mitochondrial uncoupling proteins","volume":"35","author":"Azzu","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1042\/BSR20150116","article-title":"Uncoupling protein 2 mediates resistance to gemcitabine-induced apoptosis in hepatocellular carcinoma cell lines","volume":"35","author":"Yu","year":"2015","journal-title":"Biosci. Rep."},{"key":"ref_53","first-page":"667","article-title":"Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling","volume":"29","author":"Garlid","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.3389\/fphys.2018.01060","article-title":"Uncoupling Protein 2 in Cardiovascular Health and Disease","volume":"9","author":"Tian","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s00018-013-1407-0","article-title":"UCP2, a mitochondrial protein regulated at multiple levels","volume":"71","author":"Donadelli","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1042\/BSR20160062","article-title":"Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma","volume":"36","author":"Yu","year":"2016","journal-title":"Biosci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.febslet.2007.01.010","article-title":"UCP2 is a mitochondrial transporter with an unusual very short half-life","volume":"581","author":"Rousset","year":"2007","journal-title":"FEBS Lett"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1093\/emboj\/cdg412","article-title":"A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling","volume":"22","author":"Echtay","year":"2003","journal-title":"Embo J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1016\/j.bbamcr.2016.04.013","article-title":"UCPs, at the interface between bioenergetics and metabolism","volume":"1863","author":"Bouillaud","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1073\/pnas.1317400111","article-title":"UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation","volume":"111","author":"Vozza","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"G666","DOI":"10.1152\/ajpgi.00213.2016","article-title":"A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition","volume":"312","author":"Krishnan","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.freeradbiomed.2013.05.049","article-title":"A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL\/6J mice results in mitochondrial redox abnormalities","volume":"63","author":"Ronchi","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.2337\/db16-0291","article-title":"A Direct Comparison of Metabolic Responses to High-Fat Diet in C57BL\/6J and C57BL\/6NJ Mice","volume":"65","author":"Ryan","year":"2016","journal-title":"Diabetes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2015.07.008","article-title":"Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure","volume":"22","author":"Nickel","year":"2015","journal-title":"Cell Metab."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Jakobsdottir, G., Xu, J., Molin, G., Ahrne, S., and Nyman, M. (2013). High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080476"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.bbrc.2015.06.023","article-title":"Succinate causes alpha-SMA production through GPR91 activation in hepatic stellate cells","volume":"463","author":"Li","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.3748\/wjg.v23.i15.2685","article-title":"Changes in human hepatic metabolism in steatosis and cirrhosis","volume":"23","author":"Schofield","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/s41396-018-0068-2","article-title":"Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota","volume":"12","author":"Serena","year":"2018","journal-title":"Isme J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.biochi.2017.02.008","article-title":"Genetic alterations in Krebs cycle and its impact on cancer pathogenesis","volume":"135","author":"Sajnani","year":"2017","journal-title":"Biochimie"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"13091","DOI":"10.1096\/fj.202001037R","article-title":"GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses","volume":"34","author":"Li","year":"2020","journal-title":"FASEB J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1111\/liv.14370","article-title":"Succinate-GPR-91 receptor signalling is responsible for nonalcoholic steatohepatitis-associated fibrosis: Effects of DHA supplementation","volume":"40","author":"Liu","year":"2020","journal-title":"Liver. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jhep.2007.03.016","article-title":"Succinate is a paracrine signal for liver damage","volume":"47","author":"Correa","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41590-019-0372-7","article-title":"SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity","volume":"20","author":"Keiran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/ni.1657","article-title":"Triggering the succinate receptor GPR91 on dendritic cells enhances immunity","volume":"9","author":"Rubic","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.metabol.2005.05.023","article-title":"Ketone body metabolism in lean and obese women","volume":"54","author":"Vice","year":"2005","journal-title":"Metabolism"},{"key":"ref_76","first-page":"12","article-title":"Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome","volume":"3","author":"Puchalska","year":"2018","journal-title":"JCI Insight"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Fletcher, J.A., Deja, S., Satapati, S., Fu, X., Burgess, S.C., and Browning, J.D. (2019). Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight, 5.","DOI":"10.1172\/jci.insight.127737"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5175","DOI":"10.1172\/JCI76388","article-title":"Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia","volume":"124","author":"Cotter","year":"2014","journal-title":"J. Clin. Invest."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1016\/j.jpba.2006.11.028","article-title":"Determination of reduced and oxidized glutathione in biological samples using liquid chromatography with fluorimetric detection","volume":"43","author":"Zakova","year":"2007","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1440-1746.2011.06807.x","article-title":"Susceptibility of rat non-alcoholic fatty liver to the acute toxic effect of acetaminophen","volume":"27","author":"Kucera","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-4939-2257-4_2","article-title":"Isolation and quality control of functional mitochondria","volume":"1264","author":"Hartwig","year":"2015","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6908\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:18Z","timestamp":1760163918000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,27]]},"references-count":86,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136908"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136908","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,27]]}}}