{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:30:41Z","timestamp":1792114241852,"version":"4.4.0"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is often accompanied by systemic metabolic disorders such as hyperglycemia, insulin resistance, and obesity. The relationship between NAFLD and systemic metabolic disorders has been well reviewed before, however, the metabolic changes that occur in hepatocyte itself have not been discussed. In NAFLD, many metabolic pathways have undergone significant changes in hepatocyte, such as enhanced glycolysis, gluconeogenesis, lactate production, tricarboxylic acid (TCA) cycle, and decreased ketone body production, mitochondrial respiration, and adenosine triphosphate (ATP) synthesis, which play a role in compensating or exacerbating disease progression, and there is close and complex interaction existed between these metabolic pathways. Among them, some metabolic pathways can be the potential therapeutic targets for NAFLD. A detailed summary of the metabolic characteristics of hepatocytes in the context of NAFLD helps us better understand the pathogenesis and outcomes of the disease.<\/jats:p>","DOI":"10.3389\/fphys.2021.710420","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T13:39:26Z","timestamp":1630676366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":115,"title":["Metabolic Changes of Hepatocytes in NAFLD"],"prefix":"10.3389","volume":"12","author":[{"given":"Qianrang","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiacheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusen","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.mito.2014.05.007","article-title":"Comprehensive review on lactate metabolism in human health.","volume":"17","author":"Adeva-Andany","year":"2014","journal-title":"Mitochondrion"},{"key":"B2","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.metabol.2005.09.014","article-title":"Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids.","volume":"55","author":"Bajotto","year":"2006","journal-title":"Metabolism"},{"key":"B3","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1111\/j.1478-3231.2010.02248.x","article-title":"Apoptosis is associated with CD36\/fatty acid translocase upregulation in non-alcoholic steatohepatitis.","volume":"30","author":"Bechmann","year":"2010","journal-title":"Liver Int."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1172\/jci41636","article-title":"The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans.","volume":"122","author":"Benhamed","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B5","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.mam.2004.06.004","article-title":"Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects.","volume":"25","author":"Bonnefont","year":"2004","journal-title":"Mol. Aspects Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1210\/er.2018-00064","article-title":"Molecular actions of PPAR\u03b1 in lipid metabolism and inflammation.","volume":"39","author":"Bougarne","year":"2018","journal-title":"Endocr. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1042\/bj3290191","article-title":"Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex.","author":"Bowker-Kinley","year":"1998","journal-title":"Biochem. J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.cmet.2018.03.008","article-title":"The science and translation of lactate shuttle theory.","volume":"27","author":"Brooks","year":"2018","journal-title":"Cell Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.cmet.2007.12.009","article-title":"Selective versus total insulin resistance: a pathogenic paradox.","volume":"7","author":"Brown","year":"2008","journal-title":"Cell Metab."},{"key":"B10","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1172\/jci22422","article-title":"Molecular mediators of hepatic steatosis and liver injury.","volume":"114","author":"Browning","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1002\/hep.31599","article-title":"Nonalcoholic fatty liver disease: reporting histologic findings in clinical practice.","volume":"73","author":"Brunt","year":"2020","journal-title":"Hepatology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: a multisystem disease.","author":"Byrne","year":"2015","journal-title":"J. Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.cmet.2019.03.014","article-title":"Pyruvate-carboxylase-mediated anaplerosis promotes antioxidant capacity by sustaining TCA cycle and redox metabolism in liver.","volume":"29","author":"Cappel","year":"2019","journal-title":"Cell Metab."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5692","DOI":"10.1074\/jbc.274.9.5692","article-title":"Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.","volume":"274","author":"Chavin","year":"1999","journal-title":"J. Biol. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.1002\/jcp.25998","article-title":"Involvement of the Warburg effect in non-tumor diseases processes.","volume":"233","author":"Chen","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14477","article-title":"Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance.","volume":"8","author":"Cho","year":"2017","journal-title":"Nat. Commun."},{"key":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1053\/jhep.2001.29628","article-title":"Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients.","volume":"34","author":"Crespo","year":"2001","journal-title":"Hepatology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1126\/science.143.3609.929","article-title":"Lactic dehydrogenases: functions of the two types rates of synthesis of the two major forms can be correlated with metabolic differentiation.","volume":"143","author":"Dawson","year":"1964","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01143","article-title":"Lactate in the regulation of tumor microenvironment and therapeutic approaches.","volume":"9","author":"de la Cruz-L\u00f3pez","year":"2019","journal-title":"Front. Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1093\/pcp\/pcw076","article-title":"ROS generation in peroxisomes and its role in cell signaling.","volume":"57","author":"Del R\u00edo","year":"2016","journal-title":"Plant Cell Physiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.biochi.2004.11.008","article-title":"Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver.","volume":"87","author":"Dentin","year":"2005","journal-title":"Biochimie"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1172\/jci23621","article-title":"Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Invest."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1172\/jci88894","article-title":"Distinct but complementary contributions of PPAR isotypes to energy homeostasis.","volume":"127","author":"Dubois","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B25","first-page":"614","article-title":"TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c).","volume":"232","author":"Endo","year":"2007","journal-title":"Exp. Biol. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1053\/j.gastro.2007.11.038","article-title":"Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.","volume":"134","author":"Fabbrini","year":"2008","journal-title":"Gastroenterology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.jhep.2017.06.003","article-title":"New trends on obesity and NAFLD in Asia.","volume":"67","author":"Fan","year":"2017","journal-title":"J. Hepatol."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.127737","article-title":"Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver.","volume":"5","author":"Fletcher","year":"2019","journal-title":"JCI Insight"},{"key":"B29","doi-asserted-by":"publisher","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":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31843","article-title":"Saroglitazar, a PPAR-\u03b1\/\u03b3 agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial.","author":"Gawrieh","year":"2021","journal-title":"Hepatology."},{"key":"B31","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1113\/jphysiol.2003.058701","article-title":"Lactate metabolism: a new paradigm for the third millennium.","author":"Gladden","year":"2004","journal-title":"J. Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2876","DOI":"10.2337\/db16-0223","article-title":"Inhibition of pyruvate dehydrogenase kinase 2 protects against hepatic steatosis through modulation of tricarboxylic acid cycle anaplerosis and ketogenesis.","volume":"65","author":"Go","year":"2016","journal-title":"Diabetes"},{"key":"B33","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nrm.2017.89","article-title":"Biochemical and cellular properties of insulin receptor signalling.","volume":"19","author":"Haeusler","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1146\/annurev.bi.52.070183.003153","article-title":"Gluconeogenesis and related aspects of glycolysis.","volume":"52","author":"Hers","year":"1983","journal-title":"Annu. Rev. Biochem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1016\/j.biotechadv.2018.03.003","article-title":"Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR.","volume":"36","author":"Hiebl","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1111\/j.1872-034X.2008.00382.x","article-title":"Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease.","volume":"38","author":"Higuchi","year":"2008","journal-title":"Hepatol. Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1073\/pnas.1213773111","article-title":"Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.","volume":"111","author":"Hodakoski","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1172\/jci20513","article-title":"Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.","volume":"113","author":"Horie","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B39","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1053\/j.gastro.2010.05.039","article-title":"Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals.","volume":"139","author":"Iozzo","year":"2010","journal-title":"Gastroenterology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1007\/s00535-013-0758-5","article-title":"Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.","volume":"48","author":"Kawano","year":"2013","journal-title":"J. Gastroenterol."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1042\/bsr20160381","article-title":"Hepatic glucose utilization in hepatic steatosis and obesity.","volume":"36","author":"Keramida","year":"2016","journal-title":"Biosci. Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1002\/hep.30429","article-title":"Modulation of insulin resistance in nonalcoholic fatty liver disease.","volume":"70","author":"Khan","year":"2019","journal-title":"Hepatology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1172\/jci23606","article-title":"FGF-21 as a novel metabolic regulator.","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Invest."},{"key":"B44","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.cmet.2010.06.009","article-title":"Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis.","volume":"12","author":"Kim","year":"2010","journal-title":"Cell Metab."},{"key":"B45","first-page":"351","article-title":"Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.","volume":"20","author":"Kohjima","year":"2007","journal-title":"Int. J. Mol. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.cmet.2015.04.004","article-title":"Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.","volume":"21","author":"Koliaki","year":"2015","journal-title":"Cell Metab."},{"key":"B47","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrc3038","article-title":"Otto Warburg\u2019s contributions to current concepts of cancer metabolism.","volume":"11","author":"Koppenol","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1016\/j.bbadis.2018.03.003","article-title":"Deletion of NLRX1 increases fatty acid metabolism and prevents diet-induced hepatic steatosis and metabolic syndrome.","author":"Kors","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1053\/j.gastro.2013.11.049","article-title":"Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.","volume":"146","author":"Lambert","year":"2014","journal-title":"Gastroenterology"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1016\/j.cgh.2018.04.042","article-title":"Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis.","volume":"16","author":"Lawitz","year":"2018","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1002\/path.5131","article-title":"Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose\/fatty acid preference under high-fat diet conditions.","volume":"246","author":"Liu","year":"2018","journal-title":"J. Pathol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1053\/j.gastro.2018.07.027","article-title":"GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.","volume":"155","author":"Loomba","year":"2018","journal-title":"Gastroenterology"},{"key":"B53","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1002\/hep.31622","article-title":"Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH.","volume":"73","author":"Loomba","year":"2021","journal-title":"Hepatology"},{"key":"B54","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.canlet.2014.04.001","article-title":"The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism.","author":"Lu","year":"2015","journal-title":"Cancer Lett."},{"key":"B55","doi-asserted-by":"publisher","first-page":"7347","DOI":"10.1073\/pnas.1922344117","article-title":"Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease.","volume":"117","author":"Luukkonen","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B56","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1053\/j.gastro.2018.06.083","article-title":"Mitochondrial dysfunction and signaling in chronic liver diseases.","volume":"155","author":"Mansouri","year":"2018","journal-title":"Gastroenterology"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease.","volume":"11","author":"Mart\u00ednez-Reyes","year":"2020","journal-title":"Nat. Commun."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2335","DOI":"10.1111\/j.1572-0241.2003.07725.x","article-title":"Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13C-octanoate breath test.","volume":"98","author":"Miele","year":"2003","journal-title":"Am. J. Gastroenterol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1111\/j.1572-0241.2003.07221.x","article-title":"Hepatic ATP reserve and efficiency of replenishing: comparison between obese and nonobese normal individuals.","volume":"98","author":"Nair","year":"2003","journal-title":"Am. J. Gastroenterol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"30409","DOI":"10.1074\/jbc.R200006200","article-title":"The key role of anaplerosis and cataplerosis for citric acid cycle function.","volume":"277","author":"Owen","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1667","article-title":"PPAR\u03b3 contributes to PKM2 and HK2 expression in fatty liver.","volume":"3","author":"Panasyuk","year":"2012","journal-title":"Nat. Commun."},{"key":"B62","doi-asserted-by":"publisher","first-page":"E484","DOI":"10.1152\/ajpendo.00492.2015","article-title":"Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity.","volume":"310","author":"Patterson","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"B63","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1053\/jhep.2003.50398","article-title":"Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis.","volume":"38","author":"P\u00e9rez-Carreras","year":"2003","journal-title":"Hepatology"},{"key":"B64","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of insulin action and insulin resistance.","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"B65","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/nrendo.2017.80","article-title":"Regulation of hepatic glucose metabolism in health and disease.","volume":"13","author":"Petersen","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1016\/j.ymthe.2019.06.017","article-title":"A mitochondrial VDAC1-based peptide greatly suppresses steatosis and NASH-associated pathologies in a mouse model.","volume":"27","author":"Pittala","year":"2019","journal-title":"Mol. Ther."},{"key":"B67","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","article-title":"Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics.","volume":"25","author":"Puchalska","year":"2017","journal-title":"Cell Metab."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1053\/j.gastro.2016.01.038","article-title":"Elafibranor, an agonist of the peroxisome proliferator-activated receptor-\u03b1 and -\u03b4, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.","volume":"150","author":"Ratziu","year":"2016","journal-title":"Gastroenterology"},{"key":"B69","doi-asserted-by":"publisher","first-page":"G1333","DOI":"10.1152\/ajpgi.2001.281.6.G1333","article-title":"Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis.","volume":"281","author":"Reddy","year":"2001","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"2819","DOI":"10.1101\/gad.844900","article-title":"Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.","volume":"14","author":"Repa","year":"2000","journal-title":"Genes Dev."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bse0470001","article-title":"The mitochondrial respiratory chain.","volume":"47","author":"Rich","year":"2010","journal-title":"Essays Biochem."},{"key":"B72","doi-asserted-by":"publisher","first-page":"G1135","DOI":"10.1152\/ajpgi.2001.281.5.G1135","article-title":"Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress.","volume":"281","author":"Robertson","year":"2001","journal-title":"Am. J. Physiol Gastrointest. Liver Physiol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1152\/physrev.1980.60.1.143","article-title":"Physiological roles of ketone bodies as substrates and signals in mammalian tissues.","volume":"60","author":"Robinson","year":"1980","journal-title":"Physiol. Rev."},{"key":"B74","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1126\/science.1948033","article-title":"Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR.","volume":"254","author":"Rothman","year":"1991","journal-title":"Science"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3390\/nu11123064","article-title":"Evaluation of dietary approaches for the treatment of non-alcoholic fatty liver disease: a systematic review.","volume":"11","author":"Saeed","year":"2019","journal-title":"Nutrients"},{"key":"B76","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.1016\/s0140-6736(10)60408-4","article-title":"Lipid-induced insulin resistance: unravelling the mechanism.","volume":"375","author":"Samuel","year":"2010","journal-title":"Lancet"},{"key":"B77","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1172\/jci77812","article-title":"The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.","volume":"126","author":"Samuel","year":"2016","journal-title":"J. Clin. Invest."},{"key":"B78","doi-asserted-by":"publisher","first-page":"2705","DOI":"10.1016\/s0140-6736(18)31785-9","article-title":"Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial.","volume":"392","author":"Sanyal","year":"2019","journal-title":"Lancet"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1053\/gast.2001.23256","article-title":"Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.","volume":"120","author":"Sanyal","year":"2001","journal-title":"Gastroenterology"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1172\/jci86695","article-title":"Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver.","volume":"126","author":"Satapati","year":"2016","journal-title":"J. Clin. Invest."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1194\/jlr.M023382","article-title":"Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver.","volume":"53","author":"Satapati","year":"2012","journal-title":"J. Lipid Res."},{"key":"B82","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1136\/gut.2007.147496","article-title":"Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury.","volume":"57","author":"Serviddio","year":"2008","journal-title":"Gut"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101154","article-title":"Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease.","volume":"45","author":"Shannon","year":"2021","journal-title":"Mol. Metab."},{"key":"B84","doi-asserted-by":"publisher","first-page":"30028","DOI":"10.1074\/jbc.274.42.30028","article-title":"Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus.","volume":"274","author":"Shimomura","year":"1999","journal-title":"J. Biol. Chem."},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.272re3","article-title":"CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.","volume":"2","author":"Silverstein","year":"2009","journal-title":"Sci. Signal."},{"key":"B86","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.cgh.2014.04.014","article-title":"Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.","volume":"13","author":"Singh","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.cmet.2011.11.004","article-title":"Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease.","volume":"14","author":"Sunny","year":"2011","journal-title":"Cell Metab."},{"key":"B88","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.jhep.2011.06.010","article-title":"Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review.","volume":"56","author":"Thoma","year":"2012","journal-title":"J. Hepatol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","article-title":"NAFLD and diabetes mellitus.","volume":"14","author":"Tilg","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.cmet.2020.10.026","article-title":"The power of plasticity-metabolic regulation of hepatic stellate cells.","volume":"33","author":"Trivedi","year":"2021","journal-title":"Cell Metab."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: the metabolic requirements of cell proliferation.","volume":"324","author":"Vander Heiden","year":"2009","journal-title":"Science"},{"key":"B92","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1111\/j.1742-4658.2010.07947.x","article-title":"Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans.","volume":"278","author":"Wanders","year":"2011","journal-title":"FEBS J."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1016\/j.jhep.2020.11.028","article-title":"Acetylation of lactate dehydrogenase B drives NAFLD progression by impairing lactate clearance.","volume":"74","author":"Wang","year":"2020","journal-title":"J. Hepatol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/nrm4074","article-title":"Transcriptional regulation of hepatic lipogenesis.","volume":"16","author":"Wang","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1210\/er.2019-00034","article-title":"The liver as an endocrine organ-linking NAFLD and insulin resistance.","volume":"40","author":"Watt","year":"2019","journal-title":"Endocr. Rev."},{"key":"B96","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.cmet.2015.06.006","article-title":"Redox homeostasis and mitochondrial dynamics.","volume":"22","author":"Willems","year":"2015","journal-title":"Cell Metab."},{"key":"B97","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.hbpd.2020.02.010","article-title":"Associations between obesity and metabolic health with nonalcoholic fatty liver disease in elderly Chinese.","volume":"19","author":"Wu","year":"2020","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"B98","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B99","doi-asserted-by":"publisher","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":"B100","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.ejphar.2016.05.034","article-title":"The 11\u03b2-hydroxysteroid dehydrogenase type 1 inhibitor protects against the insulin resistance and hepatic steatosis in db\/db mice.","volume":"788","author":"Yuan","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"14802","DOI":"10.1073\/pnas.011597698","article-title":"The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes.","volume":"98","author":"Zhou","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B102","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.","volume":"94","author":"Zorov","year":"2014","journal-title":"Physiol. Rev."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.710420\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T13:39:30Z","timestamp":1630676370000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.710420\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":102,"alternative-id":["10.3389\/fphys.2021.710420"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.710420","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]},"article-number":"710420"}}