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Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway

Cited 41 time in Web of Science Cited 39 time in Scopus
Authors
Bae, Eun Ju; Yang, Yoon Mee; Kim, Jin Wan; Kim, Sang Geon
Issue Date
2007-08-03
Publisher
Wiley-Blackwell
Citation
Hepatology 2007;46:730-739
Keywords
AMP-Activated Protein KinasesAnimalsCell LineGlucose/metabolismHypoglycemia/chemically inducedInsulin/pharmacology*Insulin ResistanceLeptin/geneticsLiver/*drug effects/enzymologyMiceMice, Mutant StrainsMultienzyme Complexes/genetics/metabolismPhosphorylationProtein-Serine-Threonine Kinases/genetics/metabolismPyrazines/*pharmacologyRibosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitorsThiones/*isolation & purification/*pharmacologyTransfectionTransforming Growth Factor alpha/*antagonists & inhibitors
Abstract
Several established liver diseases of various causes are highly associated with hepatic insulin resistance, which is characterized by the desensitization of target cells to insulin. Peripheral insulin resistance is observed in most patients who have cirrhosis. Conversely, insulin-resistant diabetic patients are at increased risk for developing liver disease. Current therapeutic interventions in insulin resistance are limited and therefore likely to be advanced by new tailor-made drugs. Oltipraz, a prototype dithiolthione, inhibits transforming growth factor beta1 and has the ability to regenerate cirrhotic liver. We investigated the effects of oltipraz and synthetic dithiolthiones on hepatic insulin resistance and the molecular basis of action. Oltipraz and other dithiolethione compounds were tested on tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance and glucose homeostasis in vitro and in vivo via immunoblotting, plasmid transfection, kinase analysis, and functional assays. Oltipraz treatment inhibited the ability of TNF-alpha to activate p70 ribosomal S6 kinase-1 (S6K1) downstream of mammalian target of rapamycin, thus preventing insulin receptor substrate-1 serine phosphorylation and protecting insulin signals. Moreover, oltipraz activated AMP-activated protein kinase (AMPK), whose inhibition by a dominant negative mutant abolished S6K1 inhibition and protected insulin signaling, indicating that AMPK activation leads to S6K1 inhibition. In hepatocyte-derived cell lines, oltipraz inhibited glucose production. Oltipraz prevented hepatic insulin resistance in C57BL/6 mice challenged with endotoxin (or TNF-alpha), leptin-deficient mice, and mice fed a high-fat diet. Synthetic dithiolethiones comparably inhibited insulin resistance. CONCLUSION: Our findings led to the identification of dithiolethione compounds that prevent insulin resistance through a mechanism involving AMPK-mediated S6K1 inhibition and thereby sensitize hepatic insulin response.
ISSN
0270-9139 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17668885

http://hdl.handle.net/10371/21303
DOI
https://doi.org/10.1002/hep.21769
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College of Medicine/School of Medicine (의과대학/대학원)Program in Clinical Pharmacology (협동과정-임상약리학전공)Journal Papers (저널논문_협동과정-임상약리학전공)
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