{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:07:11Z","timestamp":1792814831527,"version":"4.5.0"},"reference-count":131,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Basilicata","award":["1020501012020RIL"],"award-info":[{"award-number":["1020501012020RIL"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The strong relationship between metabolic alterations and non-alcoholic steatohepatitis (NASH) suggests a pathogenic interplay. However, many aspects have not yet been fully clarified. Nowadays, NASH is becoming the main cause of liver-associated morbidity and mortality. Therefore, an effort to understand the mechanisms underlying the pathogenesis of NASH is critical. Among the nuclear receptor transcription factors, peroxisome-proliferator-activated receptor alpha (PPAR\u03b1) is highly expressed in the liver, where it works as a pivotal transcriptional regulator of the intermediary metabolism. In this context, PPAR\u03b1\u2019s function in regulating the lipid metabolism is essential for proper liver functioning. Here, we review metabolic liver genes under the control of PPAR\u03b1 and discuss how this aspect can impact the inflammatory condition and pathogenesis of NASH.<\/jats:p>","DOI":"10.3390\/biology11050792","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T22:57:22Z","timestamp":1653346642000},"page":"792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH)"],"prefix":"10.3390","volume":"11","author":[{"given":"Simona","family":"Todisco","sequence":"first","affiliation":[{"name":"Department of Science, University of Basilicata, Viale dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8455-4075","authenticated-orcid":false,"given":"Anna","family":"Santarsiero","sequence":"additional","affiliation":[{"name":"Department of Science, University of Basilicata, Viale dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Convertini","sequence":"additional","affiliation":[{"name":"Department of Science, University of Basilicata, Viale dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"De Stefano","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, San Carlo Hospital, Via Potito Petrone, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Gilio","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, San Carlo Hospital, Via Potito Petrone, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Iacobazzi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8509-5218","authenticated-orcid":false,"given":"Vittoria","family":"Infantino","sequence":"additional","affiliation":[{"name":"Department of Science, University of Basilicata, Viale dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.4254\/wjh.v9.i16.715","article-title":"Non-alcoholic fatty liver disease: An expanded review","volume":"9","author":"Benedict","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/hep.21496","article-title":"The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD","volume":"45","author":"Angulo","year":"2007","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"44495","DOI":"10.1074\/jbc.M105945200","article-title":"p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: A potential role in the cardiac metabolic stress response","volume":"276","author":"Barger","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1006\/bbrc.1994.1222","article-title":"Structure of the mouse peroxisome proliferator activated receptor alpha gene","volume":"199","author":"Gearing","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/ncpcardio1278","article-title":"Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease","volume":"5","author":"Staels","year":"2008","journal-title":"Nat. Clin. Pract. Cardiovasc. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1002\/hep.26461","article-title":"Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha\/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"58","author":"Staels","year":"2013","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.bbagrm.2016.03.002","article-title":"Nuclear receptors and nonalcoholic fatty liver disease","volume":"1859","author":"Cave","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1210\/endo.137.1.8536636","article-title":"Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat","volume":"137","author":"Braissant","year":"1996","journal-title":"Endocrinology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.biochi.2016.11.009","article-title":"PPARs and nonalcoholic fatty liver disease","volume":"136","author":"Liss","year":"2017","journal-title":"Biochimie"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.molmet.2014.02.002","article-title":"Integrated physiology and systems biology of PPARalpha","volume":"3","author":"Kersten","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/35013000","article-title":"Roles of PPARs in health and disease","volume":"405","author":"Kersten","year":"2000","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1172\/JCI200420468","article-title":"PPARalpha governs glycerol metabolism","volume":"114","author":"Patsouris","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271983","DOI":"10.1155\/2015\/271983","article-title":"Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions","volume":"2015","author":"Lee","year":"2015","journal-title":"PPAR Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s000110050622","article-title":"Peroxisome proliferator-activated receptors (PPARs): Nuclear receptors at the crossroads between lipid metabolism and inflammation","volume":"49","author":"Chinetti","year":"2000","journal-title":"Inflamm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1096\/fj.01-0147com","article-title":"The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism","volume":"15","author":"Kersten","year":"2001","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.cmet.2007.05.002","article-title":"Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states","volume":"5","author":"Badman","year":"2007","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jhep.2014.10.039","article-title":"Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease","volume":"62","author":"Pawlak","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1136\/gutjnl-2015-310798","article-title":"Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD","volume":"65","author":"Montagner","year":"2016","journal-title":"Gut"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20","DOI":"10.2174\/1871525716666180528100002","article-title":"Free Fatty Acids: Circulating Contributors of Metabolic Syndrome","volume":"16","author":"Suiter","year":"2018","journal-title":"Cardiovasc. Hematol. Agents Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.2174\/13816128113199990344","article-title":"Pathophysiology of NASH: Perspectives for a targeted treatment","volume":"19","author":"Marra","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6184","DOI":"10.3390\/ijms15046184","article-title":"Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease","volume":"15","author":"Jung","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/biof.48","article-title":"Reactive oxygen species and peroxisomes: Struggling for balance","volume":"35","author":"Bonekamp","year":"2009","journal-title":"Biofactors"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9547613","DOI":"10.1155\/2018\/9547613","article-title":"Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease","volume":"2018","author":"Masarone","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/978-94-007-6889-5_13","article-title":"Role of peroxisomes as a source of reactive oxygen species (ROS) signaling molecules","volume":"69","author":"Sandalio","year":"2013","journal-title":"Subcell. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3109\/10715762.2013.837577","article-title":"Involvement of free radicals and oxidative stress in NAFLD\/NASH","volume":"47","author":"Sumida","year":"2013","journal-title":"Free Radic. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/347645a0","article-title":"Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators","volume":"347","author":"Issemann","year":"1990","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1126\/science.294.5548.1866","article-title":"Nuclear receptors and lipid physiology: Opening the X-files","volume":"294","author":"Chawla","year":"2001","journal-title":"Science"},{"key":"ref_28","first-page":"1173","article-title":"Transcription factors 3: Nuclear receptors","volume":"2","author":"Gronemeyer","year":"1995","journal-title":"Protein Profile"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ejmech.2019.01.067","article-title":"Role of PPAR receptor in different diseases and their ligands: Physiological importance and clinical implications","volume":"166","author":"Mirza","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12933-019-0864-7","article-title":"The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMalpha) paradigm: Conceptual framework and therapeutic potential: A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation","volume":"18","author":"Fruchart","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3945\/an.111.001602","article-title":"Mechanisms of gene regulation by fatty acids","volume":"3","author":"Georgiadi","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.mpaic.2009.03.011","article-title":"Metabolic functions of the liver","volume":"10","author":"Mitra","year":"2009","journal-title":"Anaesth. Intensive Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.bbadis.2018.10.018","article-title":"Epigenetic upregulation and functional role of the mitochondrial aspartate\/glutamate carrier isoform 1 in hepatocellular carcinoma","volume":"1865","author":"Infantino","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Infantino, V., Santarsiero, A., Convertini, P., Todisco, S., and Iacobazzi, V. (2021). Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115703"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Todisco, S., Convertini, P., Iacobazzi, V., and Infantino, V. (2019). TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma. Cancers, 12.","DOI":"10.3390\/cancers12010068"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0092-8674(94)90252-6","article-title":"Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein","volume":"79","author":"Schaffer","year":"1994","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1210\/en.2015-1866","article-title":"Hepatocyte-Specific Disruption of CD36 Attenuates Fatty Liver and Improves Insulin Sensitivity in HFD-Fed Mice","volume":"157","author":"Wilson","year":"2016","journal-title":"Endocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1194\/jlr.R056705","article-title":"Recent insights into the biological functions of liver fatty acid binding protein 1","volume":"56","author":"Wang","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.jnutbio.2010.01.005","article-title":"Liver fatty acid-binding protein and obesity","volume":"21","author":"Atshaves","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1194\/jlr.M039867","article-title":"Hepatic ATGL mediates PPAR-alpha signaling and fatty acid channeling through an L-FABP independent mechanism","volume":"55","author":"Ong","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1074\/jbc.273.10.5678","article-title":"Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha)","volume":"273","author":"Aoyama","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11012","DOI":"10.1073\/pnas.91.23.11012","article-title":"The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression","volume":"91","author":"Gulick","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1210\/er.2018-00064","article-title":"Molecular Actions of PPARalpha in Lipid Metabolism and Inflammation","volume":"39","author":"Bougarne","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Grabacka, M., Pierzchalska, M., Dean, M., and Reiss, K. (2016). Regulation of Ketone Body Metabolism and the Role of PPARalpha. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122093"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1126\/science.1227166","article-title":"Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor","volume":"339","author":"Shimazu","year":"2013","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5336","DOI":"10.1002\/j.1460-2075.1996.tb00918.x","article-title":"PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene","volume":"15","author":"Schoonjans","year":"1996","journal-title":"EMBO J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1463-1326.2010.01275.x","article-title":"Hepatic steatosis: A role for de novo lipogenesis and the transcription factor SREBP-1c","volume":"12","author":"Ferre","year":"2010","journal-title":"Diabetes Obes. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.bbrc.2007.02.114","article-title":"Transcription of the mitochondrial citrate carrier gene: Role of SREBP-1, upregulation by insulin and downregulation by PUFA","volume":"356","author":"Infantino","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"21466","DOI":"10.1074\/jbc.M110.209973","article-title":"Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha)","volume":"286","author":"Alvarez","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S0022-2275(20)31655-2","article-title":"Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice","volume":"42","author":"Patel","year":"2001","journal-title":"J. Lipid Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"34036","DOI":"10.1074\/jbc.M109.051052","article-title":"Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice","volume":"284","author":"Oosterveer","year":"2009","journal-title":"J. Biol Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1161\/CIRCRESAHA.110.216523","article-title":"Control of macrophage activation and function by PPARs","volume":"106","author":"Chawla","year":"2010","journal-title":"Circ. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/nri2748","article-title":"Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells","volume":"10","author":"Glass","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nri1748","article-title":"Combinatorial roles of nuclear receptors in inflammation and immunity","volume":"6","author":"Glass","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.2174\/092986705774462905","article-title":"PPARs in diseases: Control mechanisms of inflammation","volume":"12","author":"Kostadinova","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"32048","DOI":"10.1074\/jbc.274.45.32048","article-title":"Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1","volume":"274","author":"Delerive","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.bbagrm.2013.04.007","article-title":"Transcriptional control by NF-kappaB: Elongation in focus","volume":"1829","author":"Diamant","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1002\/cbic.200400144","article-title":"NF-kappaB: A multifaceted transcription factor regulated at several levels","volume":"5","author":"Schmitz","year":"2004","journal-title":"Chembiochem"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"298","DOI":"10.3177\/jnsv.54.298","article-title":"PPAR alpha and PPAR delta transactivity and p300 binding activity induced by arachidonic acid in colorectal cancer cell line Caco-2","volume":"54","author":"Mochizuki","year":"2008","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Santarsiero, A., Convertini, P., Todisco, S., Pierri, C.L., De Grassi, A., Williams, N.C., Iacobazzi, D., De Stefano, G., O\u2019Neill, L.A.J., and Infantino, V. (2021). ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-kappaB Acetylation. Cells, 10.","DOI":"10.3390\/cells10112962"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1016\/j.yexcr.2013.04.007","article-title":"PPARalpha agonist fenofibrate attenuates TNF-alpha-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway","volume":"319","author":"Wang","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s10753-013-9728-6","article-title":"The protective effect of fenofibrate against TNF-alpha-induced CD40 expression through SIRT1-mediated deacetylation of NF-kappaB in endothelial cells","volume":"37","author":"Wang","year":"2014","journal-title":"Inflammation"},{"key":"ref_63","first-page":"1029","article-title":"DNA binding-independent induction of IkappaBalpha gene transcription by PPARalpha","volume":"16","author":"Delerive","year":"2002","journal-title":"Mol. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"36703","DOI":"10.1074\/jbc.M004045200","article-title":"Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators","volume":"275","author":"Delerive","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1042\/BJ20050964","article-title":"Peroxisome-proliferator-activated receptor alpha agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1","volume":"395","author":"Grau","year":"2006","journal-title":"Biochem. J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1097\/00001756-200505310-00010","article-title":"PPAR-alpha activators suppress STAT1 inflammatory signaling in lipopolysaccharide-activated rat glia","volume":"16","author":"Lee","year":"2005","journal-title":"Neuroreport"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1124\/mol.64.2.355","article-title":"Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma","volume":"64","author":"Shipley","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.taap.2003.12.020","article-title":"Simultaneous, bidirectional inhibitory crosstalk between PPAR and STAT5b","volume":"199","author":"Shipley","year":"2004","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"32833","DOI":"10.1074\/jbc.273.49.32833","article-title":"Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging","volume":"273","author":"Poynter","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4350965","DOI":"10.1155\/2016\/4350965","article-title":"ROS and ROS-Mediated Cellular Signaling","volume":"2016","author":"Zhang","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1084\/jem.20021384","article-title":"Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation","volume":"198","author":"Woerly","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1385\/IR:28:1:25","article-title":"The function role of GATA-3 in Th1 and Th2 differentiation","volume":"28","author":"Zhou","year":"2003","journal-title":"Immunol. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1177\/1091581810376674","article-title":"WY-14 643, a selective PPAR{alpha} agonist, induces proinflammatory and proangiogenic responses in human ocular cells","volume":"29","author":"Zhang","year":"2010","journal-title":"Int. J. Toxicol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1161\/01.RES.87.6.516","article-title":"Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells","volume":"87","author":"Lee","year":"2000","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3488","DOI":"10.1128\/IAI.67.7.3488-3493.1999","article-title":"Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia","volume":"67","author":"Hill","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"978","DOI":"10.4049\/jimmunol.161.2.978","article-title":"Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: Correlation with induction of heme oxygenase 1","volume":"161","author":"Qureshi","year":"1998","journal-title":"J. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Rakhshandehroo, M., Hooiveld, G., Muller, M., and Kersten, S. (2009). Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006796"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Thomas, M., Bayha, C., Klein, K., Muller, S., Weiss, T.S., Schwab, M., and Zanger, U.M. (2015). The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPARalpha-tr, autonomously regulates proliferative and pro-inflammatory genes. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1500-x"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.2337\/db07-0156","article-title":"Genes involved in fatty acid partitioning and binding, lipolysis, monocyte\/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects","volume":"56","author":"Westerbacka","year":"2007","journal-title":"Diabetes"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jhep.2015.02.019","article-title":"PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis","volume":"63","author":"Francque","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.biochi.2016.12.019","article-title":"The role and regulation of the peroxisome proliferator activated receptor alpha in human liver","volume":"136","author":"Kersten","year":"2017","journal-title":"Biochimie"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"376","DOI":"10.4093\/dmj.2016.40.5.376","article-title":"Statins Increase Mitochondrial and Peroxisomal Fatty Acid Oxidation in the Liver and Prevent Non-Alcoholic Steatohepatitis in Mice","volume":"40","author":"Park","year":"2016","journal-title":"Diabetes Metab. J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.cyto.2012.10.007","article-title":"Tumour necrosis factor alpha down-regulates the expression of peroxisome proliferator activated receptor alpha (PPARalpha) in human hepatocarcinoma HepG2 cells by activation of NF-kappaB pathway","volume":"61","author":"Lim","year":"2013","journal-title":"Cytokine"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1016\/j.biocel.2007.05.015","article-title":"Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT\/enhancer-binding proteins in hepatocytes","volume":"39","author":"Chew","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \u201chits\u201d?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"G852","DOI":"10.1152\/ajpgi.00521.2005","article-title":"Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation","volume":"290","author":"Reddy","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1172\/JCI6223","article-title":"Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting","volume":"103","author":"Kersten","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4753","DOI":"10.1210\/jc.2006-0587","article-title":"Review: The role of insulin resistance in nonalcoholic fatty liver disease","volume":"91","author":"Utzschneider","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.2337\/diabetes.50.8.1844","article-title":"Nonalcoholic fatty liver disease: A feature of the metabolic syndrome","volume":"50","author":"Marchesini","year":"2001","journal-title":"Diabetes"},{"key":"ref_90","doi-asserted-by":"crossref","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. Investig."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.gene.2004.06.015","article-title":"Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model","volume":"340","author":"Kim","year":"2004","journal-title":"Gene"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1210\/en.2005-1132","article-title":"Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression","volume":"147","author":"Patsouris","year":"2006","journal-title":"Endocrinology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1530\/eje.1.01821","article-title":"Plasma adiponectin is decreased in nonalcoholic fatty liver disease","volume":"152","author":"Pagano","year":"2005","journal-title":"Eur. J. Endocrinol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nm1166","article-title":"Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB","volume":"11","author":"Cai","year":"2005","journal-title":"Nat. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1194\/jlr.R005959","article-title":"Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism","volume":"51","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.2337\/db12-1397","article-title":"Activation of PPARalpha ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress","volume":"62","author":"Chan","year":"2013","journal-title":"Diabetes"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1006\/excr.2001.5266","article-title":"Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidase null mice","volume":"268","author":"Cook","year":"2001","journal-title":"Exp. Cell Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1016\/j.bbamcr.2006.09.006","article-title":"Peroxisomes and oxidative stress","volume":"1763","author":"Schrader","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.redox.2015.02.003","article-title":"H2O2 release from the very long chain acyl-CoA dehydrogenase","volume":"4","author":"Kakimoto","year":"2015","journal-title":"Redox Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"317","DOI":"10.4196\/kjpp.2017.21.3.317","article-title":"Endogenous catalase delays high-fat diet-induced liver injury in mice","volume":"21","author":"Piao","year":"2017","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.bbadis.2012.04.006","article-title":"Genetics and molecular basis of human peroxisome biogenesis disorders","volume":"1822","author":"Waterham","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.bbamcr.2015.09.035","article-title":"Hepatic dysfunction in peroxisomal disorders","volume":"1863","author":"Baes","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1016\/j.biochi.2011.06.034","article-title":"Hepatosteatosis in peroxisome deficient liver despite increased beta-oxidation capacity and impaired lipogenesis","volume":"93","author":"Peeters","year":"2011","journal-title":"Biochimie"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"31011","DOI":"10.1074\/jbc.M110.127159","article-title":"Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state","volume":"285","author":"Hall","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ceca.2016.05.004","article-title":"Interfaces between mitochondrial dynamics and disease","volume":"60","author":"Mishra","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.cell.2012.02.035","article-title":"Mitochondria: In sickness and in health","volume":"148","author":"Nunnari","year":"2012","journal-title":"Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/imm.12659","article-title":"The contribution of the citrate pathway to oxidative stress in Down syndrome","volume":"149","author":"Convertini","year":"2016","journal-title":"Immunology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.bbrc.2009.08.008","article-title":"Statins, fibrates and retinoic acid upregulate mitochondrial acylcarnitine carrier gene expression","volume":"388","author":"Iacobazzi","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1002\/cmdc.201402462","article-title":"On the metabolically active form of metaglidasen: Improved synthesis and investigation of its peculiar activity on peroxisome proliferator-activated receptors and skeletal muscles","volume":"10","author":"Laghezza","year":"2015","journal-title":"ChemMedChem"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"26839","DOI":"10.1155\/2007\/26839","article-title":"Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling","volume":"2007","author":"Rakhshandehroo","year":"2007","journal-title":"PPAR Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1016\/j.bbabio.2007.07.001","article-title":"PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation","volume":"1767","author":"Ferdinandusse","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1096\/fj.08-119420","article-title":"Metabolic profiling of PPARalpha\u2212\/\u2212 mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation","volume":"23","author":"Makowski","year":"2009","journal-title":"FASEB J."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Sanderson, L.M., de Groot, P.J., Hooiveld, G.J., Koppen, A., Kalkhoven, E., Muller, M., and Kersten, S. (2008). Effect of synthetic dietary triglycerides: A novel research paradigm for nutrigenomics. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001681"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"18767","DOI":"10.1016\/S0021-9258(17)32234-2","article-title":"Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids","volume":"269","author":"Rodriguez","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_115","first-page":"517","article-title":"Mitochondrial ROS Metabolism: 10 Years Later","volume":"80","author":"Andreyev","year":"2015","journal-title":"Biochemistry"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Marsico, M., Santarsiero, A., Pappalardo, I., Convertini, P., Chiummiento, L., Sardone, A., Di Noia, M.A., Infantino, V., and Todisco, S. (2021). Mitochondria-Mediated Apoptosis of HCC Cells Triggered by Knockdown of Glutamate Dehydrogenase 1: Perspective for Its Inhibition through Quercetin and Permethylated Anigopreissin A. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111664"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/S0168-8278(99)80243-8","article-title":"A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis","volume":"31","author":"Basaranoglu","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.dld.2007.10.002","article-title":"A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease","volume":"40","author":"Colina","year":"2008","journal-title":"Dig. Liver Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1210\/jc.2009-2622","article-title":"Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease","volume":"95","author":"Fabbrini","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3C","DOI":"10.1016\/j.amjcard.2006.11.016","article-title":"Safety considerations with fibrate therapy","volume":"99","author":"Davidson","year":"2007","journal-title":"Am. J. Cardiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"192","DOI":"10.4082\/kjfm.2017.38.4.192","article-title":"Effect of Fenofibrate Medication on Renal Function","volume":"38","author":"Kim","year":"2017","journal-title":"Korean J. Fam. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nrendo.2009.151","article-title":"Myopathy with statin-fibrate combination therapy: Clinical considerations","volume":"5","author":"Jacobson","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"7818","DOI":"10.1038\/s41598-020-64902-8","article-title":"Pemafibrate, a selective PPARalpha modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content","volume":"10","author":"Sasaki","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1111\/hepr.13571","article-title":"Effect of pemafibrate on fatty acid levels and liver enzymes in non-alcoholic fatty liver disease patients with dyslipidemia: A single-arm, pilot study","volume":"50","author":"Seko","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1111\/apt.16596","article-title":"Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMalpha), versus placebo in patients with non-alcoholic fatty liver disease","volume":"54","author":"Nakajima","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.2337\/dc12-2012","article-title":"Dual peroxisome proliferator-activated receptor alpha\/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects","volume":"36","author":"Cariou","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12933-019-0884-3","article-title":"New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: Integrated analysis of the real world evidence","volume":"18","author":"Kaul","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1053\/j.gastro.2016.01.038","article-title":"Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening","volume":"150","author":"Ratziu","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1002\/hep.31843","article-title":"Saroglitazar, a PPAR-alpha\/gamma Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial","volume":"74","author":"Gawrieh","year":"2021","journal-title":"Hepatology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3346\/jkms.2017.32.1.60","article-title":"Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness","volume":"32","author":"Lee","year":"2017","journal-title":"J. Korean Med. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1056\/NEJMoa2036205","article-title":"A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH","volume":"385","author":"Francque","year":"2021","journal-title":"N. Engl. J. 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