Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes

Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resista...

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Main Authors: Abu Bakar, M. H., Sarmidi, M. R., Tan, J. S., Mohamad Rosdi, M. N.
Format: Article
Published: Elsevier B.V. 2017
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Online Access:http://eprints.utm.my/id/eprint/76162/
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85011284948&doi=10.1016%2fj.ejphar.2017.01.043&partnerID=40&md5=225918aac909be62f8f2e3d838815f72
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spelling my.utm.761622018-06-25T09:06:08Z http://eprints.utm.my/id/eprint/76162/ Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes Abu Bakar, M. H. Sarmidi, M. R. Tan, J. S. Mohamad Rosdi, M. N. TP Chemical technology Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75�mM) for 48�h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-κB p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-α and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30�nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance. Elsevier B.V. 2017 Article PeerReviewed Abu Bakar, M. H. and Sarmidi, M. R. and Tan, J. S. and Mohamad Rosdi, M. N. (2017) Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes. European Journal of Pharmacology, 799 . pp. 73-83. ISSN 0014-2999 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85011284948&doi=10.1016%2fj.ejphar.2017.01.043&partnerID=40&md5=225918aac909be62f8f2e3d838815f72
institution Universiti Teknologi Malaysia
building UTM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Teknologi Malaysia
content_source UTM Institutional Repository
url_provider http://eprints.utm.my/
topic TP Chemical technology
spellingShingle TP Chemical technology
Abu Bakar, M. H.
Sarmidi, M. R.
Tan, J. S.
Mohamad Rosdi, M. N.
Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
description Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75�mM) for 48�h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-κB p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-α and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30�nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance.
format Article
author Abu Bakar, M. H.
Sarmidi, M. R.
Tan, J. S.
Mohamad Rosdi, M. N.
author_facet Abu Bakar, M. H.
Sarmidi, M. R.
Tan, J. S.
Mohamad Rosdi, M. N.
author_sort Abu Bakar, M. H.
title Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
title_short Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
title_full Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
title_fullStr Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
title_full_unstemmed Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes
title_sort celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in c3a hepatocytes
publisher Elsevier B.V.
publishDate 2017
url http://eprints.utm.my/id/eprint/76162/
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85011284948&doi=10.1016%2fj.ejphar.2017.01.043&partnerID=40&md5=225918aac909be62f8f2e3d838815f72
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