Fenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate-activated protein kinase-dependent induction of orphan nuclear receptor small heterodimer partner

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dc.contributor.authorD Chanda-
dc.contributor.authorChul Ho Lee-
dc.contributor.authorYong Hoon Kim-
dc.contributor.authorJung-Ran Noh-
dc.contributor.authorD K Kim-
dc.contributor.authorJ H Park-
dc.contributor.authorJung Hwan Hwang-
dc.contributor.authorM R Lee-
dc.contributor.authorK H Jeong-
dc.contributor.authorI K Lee-
dc.contributor.authorG R Kweon-
dc.contributor.authorM Shong-
dc.contributor.authorG T Oh-
dc.contributor.authorJ Y L Chiang-
dc.contributor.authorH S Choi-
dc.date.accessioned2017-04-19T09:14:29Z-
dc.date.available2017-04-19T09:14:29Z-
dc.date.issued2009-
dc.identifier.issn0270-9139-
dc.identifier.uri10.1002/hep.23049ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/9087-
dc.description.abstractPlasminogen 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 α (PPARα) 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-activated protein kinase (AMPK) signaling pathway in a PPARα-independent manner. Administration of transforming growth factor beta (TGF-7beta;) 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 PPARα 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. Conclusion: By demonstrating that a PPARα-independent feno-fibrate-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.-
dc.publisherWiley-
dc.titleFenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate-activated protein kinase-dependent induction of orphan nuclear receptor small heterodimer partner-
dc.title.alternativeFenofibrate differentially regulates plasminogen activator inhibitor-1 gene expression via adenosine monophosphate-activated protein kinase-dependent induction of orphan nuclear receptor small heterodimer partner-
dc.typeArticle-
dc.citation.titleHepatology-
dc.citation.number3-
dc.citation.endPage892-
dc.citation.startPage880-
dc.citation.volume50-
dc.contributor.affiliatedAuthorChul Ho Lee-
dc.contributor.affiliatedAuthorYong Hoon Kim-
dc.contributor.affiliatedAuthorJung-Ran Noh-
dc.contributor.affiliatedAuthorJung Hwan Hwang-
dc.contributor.alternativeNameChanda-
dc.contributor.alternativeName이철호-
dc.contributor.alternativeName김용훈-
dc.contributor.alternativeName노정란-
dc.contributor.alternativeName김돈규-
dc.contributor.alternativeName박지훈-
dc.contributor.alternativeName황정환-
dc.contributor.alternativeName이미란-
dc.contributor.alternativeName정경훈-
dc.contributor.alternativeName이인규-
dc.contributor.alternativeName권기량-
dc.contributor.alternativeName송민호-
dc.contributor.alternativeName오구택-
dc.contributor.alternativeNameChiang-
dc.contributor.alternativeName최흥식-
dc.identifier.bibliographicCitationHepatology, vol. 50, no. 3, pp. 880-892-
dc.identifier.doi10.1002/hep.23049-
dc.description.journalClassY-
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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