Fenofibrate Differentially Regulates Plasminogen Activator Inhibitor-1 Gene Expression via Adenosine Monophosphate-Activated Protein Kinase-Dependent Induction of Orphan Nuclear Receptor Small Heterodimer Partner

Title

Fenofibrate Differentially Regulates Plasminogen Activator Inhibitor-1 Gene Expression via Adenosine Monophosphate-Activated Protein Kinase-Dependent Induction of Orphan Nuclear Receptor Small Heterodimer Partner

Creator

Chanda D; Lee C H; Kim Y H; Noh J R; Kim D K; Park J H; Hwang J H; Lee M R; Jeong K H; Lee I K; Kweon G R; Shong M; Oh G T; Chiang J Y L; Choi H S

Publisher

Hepatology

Date

2009
2009-09

Description

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 alpha (PPAR alpha) 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 PPAR alpha-independent manner. Administration of transforming growth factor beta (TGF-beta) 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 alpha 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 PPAR alpha-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;50:880-892.)

Subject

cells; binding; complex; fibrosis; Gastroenterology & Hepatology; promoter; beta; mechanisms; pai-1; shp; smad3

Identifier

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

880-892

Issue

3

Volume

50

Citation

Chanda D; Lee C H; Kim Y H; Noh J R; Kim D K; Park J H; Hwang J H; Lee M R; Jeong K H; Lee I K; Kweon G R; Shong M; Oh G T; Chiang J Y L; Choi H S, “Fenofibrate Differentially Regulates Plasminogen Activator Inhibitor-1 Gene Expression via Adenosine Monophosphate-Activated Protein Kinase-Dependent Induction of Orphan Nuclear Receptor Small Heterodimer Partner,” NEOMED Bibliography Database, accessed August 5, 2021, https://neomed.omeka.net/items/show/8844.

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