Fenofibrate Reverses Palmitate Induced Impairment in Glucose Uptake in Skeletal Muscle Cells by Preventing Cytosolic Ceramide Accumulation

Bhattacharjee, Sudarshan; Das, Nandini; Mandala, Ashok; Mukhopadhyay, Satinath; Roy, Sib Sankar

doi:10.1159/000430399

Cited by 12 publications

(10 citation statements)

References 54 publications

(54 reference statements)

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“…Improvement of IR by augmentation of mitochondrial FA uptake is one of the molecular mechanisms of antidiabetic medication [36,37]. Thus reduction in muscle mitochondrial FA channeling could be responsible in part for induction of IR.…”

Section: Discussionmentioning

confidence: 99%

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

Błachnio-Zabielska

Chacińska

Vendelbo

et al. 2016

Cell Physiol Biochem

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Background/Aims: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. Methods: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U¹³C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Results: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr-treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl-Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. Conclusion: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats.

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Section: Discussionmentioning

confidence: 99%

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

Błachnio-Zabielska

Chacińska

Vendelbo

et al. 2016

Cell Physiol Biochem

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“…The cells were maintained at 37°C, and 5% CO 2 . Palmitate (PA; Sigma‐Aldrich, St. Louis, MO, USA) was conjugated with BSA prior to the treatment in serum‐starved cells . Melatonin (1 mmol/L) was provided for 30 minutes before PA treatment for 16 hours.…”

Section: Methodsmentioning

confidence: 99%

Melatonin protects against lipid‐induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice

Das

Mandala

Naaz

et al. 2017

Journal of Pineal Research

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136

126

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Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by inflammation in propagating hepatic fibrosis. The interaction of SIRT1/Mitofusin2 is critical for maintaining mitochondrial integrity and functioning, which is disrupted upon excess lipid infiltration during the progression of steatohepatitis. The complex interplay between hepatic stellate cells and steatotic hepatocytes is critically regulated by extracellular factors including increased circulating free fatty acids during fibrogenesis. Melatonin, a potent antioxidant, protects against lipid-mediated mitochondrial ROS generation. Lipotoxicity induces disruption of SIRT1 and Mitofusin2 interaction leading to mitochondrial morphological disintegration in hepatocytes. Further, fragmented mitochondria leads to mitochondrial permeability transition pore opening, cell cycle arrest and apoptosis and melatonin protects against all these lipotoxicity-mediated dysfunctions. These impaired mitochondrial dynamics also enhances the cellular glycolytic flux and reduces mitochondrial oxygen consumption rate that potentiates ROS production. High glycolytic flux generates metabolically unfavorable milieu in hepatocytes leading to inflammation, which is abrogated by melatonin. The melatonin-mediated protection against mitochondrial dysfunction was also observed in high-fat diet (HFD)-fed mice through restoration of enzymatic activities associated with respiratory chain and TCA cycle. Subsequently, melatonin reduces hepatic fat deposition and inflammation in HFD-fed mice. Thus, melatonin disrupts the interaction between steatotic hepatocyte and stellate cells, leading to the activation of the latter to abrogate collagen deposition. Altogether, the results of the current study document that the pharmacological intervention with low dose of melatonin could abrogate lipotoxicity-mediated hepatic stellate cell activation and prevent the fibrosis progression.

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“…Total RNA was isolated from cell-lines using TRI reagent (Sigma- Aldrich) following standard protocol and were processed and analyzed as previously described [31]. The list of primers used with their respective sequences and Tm are listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Co-Activation of TGFβ and Wnt Signalling Pathways Abrogates EMT in Ovarian Cancer Cells

Mitra¹,

Roy²

2017

Cell Physiol Biochem

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Background/Aims: The aggressive property of ovarian cancer (OC) in terms of epithelial-mesenchymal transition (EMT), proliferation and metastasis are of major concern. Different growth factors including TGFβ are associated with regulating these molecular events but the underlying mechanisms remain unclear. The aim of this report is to decipher the regulation of EMT by co-activation of TGFβ and Wnt signalling cascades in gaining malignancy. Methods: The expression of the different components of signalling events were analyzed by QPCR, Western blot, Immunofluorescence microscopy and flow cytometry. β-catenin promoter activity was checked by luciferase assay. Results: We observed reduced EMT in ovarian cancer cells upon co-activation with TGFβ1 and LiCl as shown by the expressions of epithelial/mesenchymal markers and the EMT promoting factor, Snail1, accompanied by decrease in the invasion and migration of the cells compared to individual pathway activation. A detailed study of the mechanism suggested reduction in the β-catenin and p-GSK3b (Ser 9) levels to be the driving cause of this phenomenon, which was reversed upon co-activation with higher concentrations of LiCl. Conclusions: Therefore, tumourigenesis might be affected by the concentration of ligand/ growth factors for the respective signalling pathways activated in the tumour microenvironment and interaction between them might alter tumourigenesis.

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Fenofibrate Reverses Palmitate Induced Impairment in Glucose Uptake in Skeletal Muscle Cells by Preventing Cytosolic Ceramide Accumulation

Cited by 12 publications

References 54 publications

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

Melatonin protects against lipid‐induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice

Co-Activation of TGFβ and Wnt Signalling Pathways Abrogates EMT in Ovarian Cancer Cells

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