{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:13:52Z","timestamp":1787166832525,"version":"build-2736575974"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2191,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Plasminogen activator inhibitor type I (PAI-1) is a marker of the fibrinolytic system and serves as a possible predictor for hepatic metabolic syndromes. Fenofibrate, a peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1) agonist, is a drug used for treatment of hyperlipidemia. Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of crucial genes involved in various metabolic pathways. In this study, we show that fenofibrate increased SHP gene expression in cultured liver cells and in the normal and diabetic mouse liver by activating the adenosine monophosphate\u2013activated protein kinase (AMPK) signaling pathway in a PPAR\u03b1-independent manner. Administration of transforming growth factor beta (TGF-\u03b2) or a methionine-deficient and choline-deficient (MCD) diet to induce the progressive fibrosing steatohepatitis model in C57BL\/6 mice was significantly reversed by fenofibrate via AMPK-mediated induction of SHP gene expression with a dramatic decrease in PAI-1 messenger RNA (mRNA) and protein expression along with other fibrotic marker genes. No reversal was observed in SHP null mice treated with fenofibrate. Treatment with another PPAR\u03b1 agonist, WY14643, showed contrasting effects on these marker gene expressions in wild-type and SHP null mice, demonstrating the specificity of fenofibrate in activating AMPK signaling. Fenofibrate exhibited a differential inhibitory pattern on PAI-1 gene expression depending on the transcription factors inhibited by SHP.\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                      By demonstrating that a PPAR\u03b1-independent fenofibrate-AMPK-SHP regulatory cascade can play a key role in PAI-1 gene down-regulation and reversal of fibrosis, our study suggests that various AMPK activators regulating SHP might provide a novel pharmacologic option in ameliorating hepatic metabolic syndromes. (Hepatology 2009.)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23049","type":"journal-article","created":{"date-parts":[[2009,4,27]],"date-time":"2009-04-27T19:47:35Z","timestamp":1240861655000},"page":"880-892","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":60,"title":["Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate\u2013activated protein kinase\u2013dependent induction of orphan nuclear receptor small heterodimer partner #"],"prefix":"10.1097","volume":"50","author":[{"given":"Dipanjan","family":"Chanda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul Ho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Hoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Ran","family":"Noh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don-Kyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hoon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Hwan","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Ran","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong-Hoon","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Kyu","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gi Ryang","family":"Kweon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minho","family":"Shong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goo-Taeg","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Y. L.","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hueng-Sik","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-28-20241201","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1126\/science.272.5266.1336","article-title":"An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors.","volume":"272","author":"Seol","year":"1996","journal-title":"Science"},{"key":"R2-28-20241201","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1507\/endocrj.K07E-103","article-title":"Molecular basis of endocrine regulation by orphan nuclear receptor small heterodimer partner.","volume":"55","author":"Chanda","year":"2008","journal-title":"Endocr J"},{"key":"R3-28-20241201","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0074-7696(07)61003-1","article-title":"Structure and function of the atypical orphan nuclear receptor small heterodimer partner.","volume":"261","author":"Lee","year":"2007","journal-title":"Int Rev Cytol"},{"key":"R4-28-20241201","doi-asserted-by":"crossref","first-page":"E368","DOI":"10.1152\/ajpendo.00800.2007","article-title":"Sodium arsenite induces orphan nuclear receptor SHP gene expression via AMPactivated protein kinase to inhibit gluconeogenic enzyme gene expression.","volume":"295","author":"Chanda","year":"2008","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"R5-28-20241201","doi-asserted-by":"crossref","first-page":"306","DOI":"10.2337\/db07-0381","article-title":"Metformin inhibits hepatic gluconeogenesis through AMPactivated protein kinase dependent regulation of the orphan nuclear receptor SHP.","volume":"57","author":"Kim","year":"2007","journal-title":"Diabetes"},{"key":"R6-28-20241201","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1172\/JCI11765","article-title":"PAI1, fibrosis, and the elusive provisional fibrin matrix.","volume":"106","author":"Loskutoff","year":"2000","journal-title":"J Clin Invest"},{"key":"R7-28-20241201","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1538-7836.2004.00827.x","article-title":"Pleiotropic functions of plasminogen activator inhibitor1.","volume":"3","author":"Lijnen","year":"2005","journal-title":"J Thromb Haemost"},{"key":"R8-28-20241201","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.2337\/dc07-0109","article-title":"Plasma PAI1 levels are increased in patients with nonalcoholic steatohepatitis.","volume":"30","author":"Targher","year":"2007","journal-title":"Diabetes Care"},{"key":"R9-28-20241201","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1182\/blood-2002-07-2331","article-title":"Direct binding of Nur77NAK1 to the plasminogen activator inhibitor 1 (PAI1) promoter regulates TNF alphainduced PAI1 expression.","volume":"101","author":"Gruber","year":"2003","journal-title":"Blood"},{"key":"R10-28-20241201","first-page":"444","article-title":"Mechanisms linking obesity with cardiovascular disease.","volume":"14","author":"Van Gaal","year":"2006","journal-title":"Nature"},{"key":"R11-28-20241201","doi-asserted-by":"crossref","first-page":"10739","DOI":"10.1016\/S0021-9258(18)82047-6","article-title":"The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor1 (PAI1) gene respond differently to interleukin1 in HepG2 cells.","volume":"268","author":"Dawson","year":"1993","journal-title":"J Biol Chem"},{"issue":"Suppl 3","key":"R12-28-20241201","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.3132\/dvdr.2007.053","article-title":"The role of fenofibrate in clinical practice.","author":"Zambon","year":"2007","journal-title":"Diab Vasc Dis Res"},{"key":"R13-28-20241201","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1016\/S0140-6736(05)67667-2","article-title":"Effects of longterm fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.","volume":"366","year":"2005","journal-title":"Lancet"},{"key":"R14-28-20241201","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1111\/j.1463-1326.2006.00668.x","article-title":"Normalization of metabolic syndrome using fenofibrate, metformin or their combination.","volume":"6","author":"Nieuwdorp","year":"2007","journal-title":"Diabetes Obes Metab"},{"key":"R15-28-20241201","doi-asserted-by":"crossref","first-page":"5479","DOI":"10.1242\/jcs.01540","article-title":"The AMPactivated protein kinase pathway: new players upstream and downstream.","volume":"117","author":"Hardie","year":"2004","journal-title":"J Cell Sci"},{"key":"R16-28-20241201","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.vph.2006.01.004","article-title":"Renoprotective effects of fenofibrate in diabetic rats are achieved by suppressing kidney plasminogen activator inhibitor1.","volume":"44","author":"Chen","year":"2006","journal-title":"Vasc Pharmacol"},{"key":"R17-28-20241201","doi-asserted-by":"crossref","first-page":"39169","DOI":"10.1074\/jbc.M605947200","article-title":"Orphan nuclear receptor small heterodimer partner inhibits transforming growth factorbeta signaling by repressing SMAD3 transactivation.","volume":"281","author":"Suh","year":"2006","journal-title":"J Biol Chem"},{"key":"R18-28-20241201","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1042\/BST0350661","article-title":"TGFbeta, Smad3 and the process of progressive fibrosis.","volume":"35","author":"Gauldie","year":"2007","journal-title":"Biochem Soc Trans"},{"key":"R19-28-20241201","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1002\/hep.20170","article-title":"Administration of the potent PPARalpha agonist, Wy14,643, reverses nutritional fibrosis and steatohepatitis in mice.","volume":"39","author":"Ip","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R20-28-20241201","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.bbrc.2006.01.052","article-title":"Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC.","volume":"341","author":"Murakami","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"R21-28-20241201","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.taap.2007.06.003","article-title":"Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration.","volume":"223","author":"Nadanaciva","year":"2007","journal-title":"Toxicol Appl Pharmacol"},{"key":"R22-28-20241201","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1161\/01.ATV.0000077401.36885.BB","article-title":"Plasma PAI1 levels are more strongly related to liver steatosis than to adipose tissue accumulation.","volume":"23","author":"Alessi","year":"2003","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"R23-28-20241201","first-page":"1492","article-title":"Autoinduction of transforming growth factor beta 1 is mediated by the AP1 complex.","volume":"10","author":"Kim","year":"1990","journal-title":"Mol Cell Biol"},{"key":"R24-28-20241201","doi-asserted-by":"crossref","first-page":"9321","DOI":"10.1074\/jbc.M808861200","article-title":"Mechanisms of resistance of hepatocyte retinoid X receptor anull mice to WY14,643induced hepatocyte proliferation and cholestasis.","volume":"284","author":"Gyamfi","year":"2009","journal-title":"J Biol Chem"},{"key":"R25-28-20241201","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1053\/j.gastro.2004.08.001","article-title":"The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.","volume":"127","author":"Fiorucci","year":"2004","journal-title":"Gastroenterology"},{"key":"R26-28-20241201","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1161\/01.ATV.0000240318.61359.e3","article-title":"Hepatocyte growth factor regulates E boxdependent plasminogen activator inhibitor type 1 gene expression in HepG2 liver cells.","volume":"26","author":"Imagawa","year":"2006","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"R27-28-20241201","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.tem.2006.05.006","article-title":"Expanding role of AMPK in endocrinology.","volume":"17","author":"Kola","year":"2006","journal-title":"Trends Endocrinol Metab"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.23049","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200909000-00028","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T08:29:08Z","timestamp":1733041748000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200909000-00028"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9]]},"references-count":27,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.23049","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2009,9]]}}}