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 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 (0.75mM) for 48h 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 30nM 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.
Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia. Electronic address: mhafizi88@usm.my.
Mohamad Hafizi
MH
Abu Bakar
Institute of Bioproduct Development, Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor, Malaysia; Innovation Centre in Agritechnology for Advanced Bioprocessing (ICA), Universiti Teknologi Malaysia, 81310, Johor Bahru, Johor, Malaysia.
Mohamad Roji
MR
Sarmidi
Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia.
Joo Shun
JS
Tan
Department of Bioprocess and Polymer Engineering, Faculty of Chemical and Energy Engineering, Universiti Teknologi Malaysia, 81310 Johor Bahru, Johor, Malaysia.
Mohamad Norisham
MN
Mohamad Rosdi
D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010168:Palmitates / Q000494:pharmacology*; D053978:Pentacyclic Triterpenes; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
D016207:Cytokines; D005227:Fatty Acids; D007328:Insulin; D016328:NF-kappa B; D010168:Palmitates; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose; C050414:celastrol
Celastrol; Hepatocytes; Inflammation; Insulin resistance; Mitochondrial dysfunction