Thioredoxin interacting protein mediates lipid-induced impairment of glucose uptake in skeletal muscle

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

doi:10.1016/j.bbrc.2016.09.168

Cited by 19 publications

(17 citation statements)

References 30 publications

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“…Knockdown or control C2C12 myotubes were starved serum for 4 h and then treated with 0.5 mmol/L PA for another 18 h, followed by stimulated with or without 100 nmol/L insulin for 10 min. We found that TXNIP knockdown markedly increased insulin-stimulated Akt phosphorylation at Thr308 ( Figures 2B,C ), GLUT4 translocation on plasma membrane ( Figure 2D ), and 2-DG uptake ( Figure 2E ), which is consistent with the previous study showing that TXNIP plays critical role in PA-induced insulin resistance ( Mandala et al, 2016 ).…”

Section: Resultssupporting

confidence: 91%

RETRACTED: Icariin Ameliorates Palmitate-Induced Insulin Resistance Through Reducing Thioredoxin-Interacting Protein (TXNIP) and Suppressing ER Stress in C2C12 Myotubes

Zhang

Cao

et al. 2018

Front. Pharmacol.

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Both thioredoxin-interacting protein (TXNIP) and endoplasmic reticulum (ER) stress are implicated in skeletal muscle insulin resistance. Icariin has been found to mimic insulin action in normal skeletal muscle C2C12 cells and display anti-diabetic properties in diet-induced obese mice. However, the underlying molecular mechanism remains to be well-established. Herein, we tested the hypothesis that the protective effects of icariin on free fatty acid-induced insulin resistance were attributed to its regulation on TXNIP protein levels and ER stress in skeletal muscle cells. We found that TXNIP mediated the saturated fatty acid palmitate (PA)-induced insulin resistance in C2C12 myotubes. Icariin treatment significantly restored PA-reduced proteasome activity resulting in reduction of TXNIP protein and suppression of ER stress, as well as improvement of insulin sensitivity. Proteasome inhibition by its specific inhibitor MG132 obviously abolished the inhibitory effect of icariin on PA-induced insulin resistance. In addition, MG132 supplementation markedly abrogated the impacts of icariin on ER stress and TXNIP-mediated downstream events such as inflammation and STAT3 phosphorylation. These results clearly indicate that icariin improves PA-induced skeletal muscle insulin resistance through a proteasome-dependent mechanism, by which icariin downregulats TXNIP levels and inhibits ER stress.

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Section: Resultssupporting

confidence: 91%

RETRACTED: Icariin Ameliorates Palmitate-Induced Insulin Resistance Through Reducing Thioredoxin-Interacting Protein (TXNIP) and Suppressing ER Stress in C2C12 Myotubes

Zhang

Cao

et al. 2018

Front. Pharmacol.

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“…TXNIP is key regulator of NLRP3 inflammasome activation, which plays an important role in liver fibrosis and hepatocellular carcinoma (Ringelhan et al, 2018;Wree et al, 2017), and its activation is associated with the NLRP3 inflammasome pathway in human diseases (Bai et al, 2019;Kim et al, 2019;Li et al, 2019). TXNIP has also emerged as an important glucose sensor that regulates glucose uptake in response to insulin (Waldhart et al, 2017) and plays an important role in metabolic stress (Mandala et al, 2016;Wu et al, 2013). Another study found that PPARA activation by fenofibrate downregulated Txnip mRNA and TXNIP protein in endothelial cells (Deng et al, 2017), suggesting the Gm15441-Txnip regulatory axis described here for liver may also function in extrahepatic tissues.…”

Section: Discussionmentioning

confidence: 75%

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Brocker

Kim

Melia

et al. 2019

Preprint

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Fasting paradigms elicit a wide-range of health benefits including suppressing inflammation.Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising new therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARA directly upregulates the long non-coding RNA gene Gm15441 through binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLRP3 inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to metabolic and inflammatory stimuli. These findings provide evidence for a novel mechanism by which PPARA attenuates hepatic inflammasome activation in response to metabolic stress through lncRNA Gm15441 induction. 4Txnip expression in vivo. Gm15441 LSL mice were treated with a PPARA agonist or fasted to assess how loss of Gm15441 impacts hepatic inflammasome activation in response to both pharmacological and physiologically-induced metabolic stress. TXNIP protein, caspase-1 (CASP1) levels, and interleukin 1 beta (IL1B) cleavage were elevated in Gm15441 LSL mice and were further increased by PPARA activation, indicating that this lncRNA plays a major role in attenuating inflammasome activation. Thus, hepatic PPARA directly regulates the lncRNA Gm15441, which in turn suppresses Txnip expression, which attenuates NLRP3 inflammasome activation during periods of metabolic stress. These studies revealed a novel regulatory mechanism supporting the beneficial effects of fasting, namely, reduced inflammation. Results LncRNA regulation by PPARA is highly tissue-specificTo assess the regulation of lncRNAs by PPARA, RNA-seq was performed using total liver RNA isolated from Ppara +/+ mice, both with and without dietary exposure to the PPARA agonist WY-14643. A lncRNA discovery pipeline was implemented that identified 15,558 liver-expressed lncRNA genes. Of these, 13,343 were intergenic, 1,966 were antisense, and 249 were intragenic lncRNAs. 44% of the 15,558 liver-expressed lncRNAs are considered novel (Melia and Waxman, 2019). Differential gene expression analysis revealed that a total of 1,735 RefSeq genes and 442 liver-expressed lncRNA genes responded to treatment with WY-14643 at an expression foldchange >2 at FDR<0.05, with 968 RefSeq genes and 245 lncRNA genes upregulated, and 767

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“…On the other hand, in the skeletal muscle, TXNIP deficiency led to a downregulation of enzymes involved in β-oxidation [ 28 ]. Interestingly, in the skeletal muscle TXNIP expression is not downregulated upon exposure to fatty acids [ 29 ]. In contrast to these two tissues, pancreatic islets do not depend on fatty acids as an energy source and therefore, β-oxidation may play a minor role in metabolism.…”

Section: Discussionmentioning

confidence: 99%

Palmitate and insulin counteract glucose-induced thioredoxin interacting protein (TXNIP) expression in insulin secreting cells via distinct mechanisms

et al. 2018

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Glucose and palmitate synergistically stimulate insulin secretion, but chronically elevated they induce apoptotic β-cell death. The glucotoxic effect has been attributed, at least partly, to the upregulation of the oxidative stress marker thioredoxin interacting protein (TXNIP). Palmitate downregulates TXNIP expression, the functional significance of which is still under debate. This study examines the mechanism and consequence of palmitate-mediated TXNIP regulation in insulin secreting cells. Palmitate (600 μM) reduced TXNIP mRNA levels in isolated human and mouse islets independently of FFAR1/GPR40. Similar effects of palmitate were observed in INS-1E cells and mimicked by other long chain fatty acids. The lowering of TXNIP mRNA was significant already 1 h after addition of palmitate, persisted for 24 h and was directly translated to changes in TXNIP protein. The pharmacological inhibition of palmitate-induced phosphorylation of AMPK, ERK1/2, JNK and PKCα/β by BML-275, PD98059, SP600125 and Gö6976, respectively, did not abolish palmitate-mediated TXNIP downregulation. The effect of palmitate was superimposed by a time-dependent (8 h and 24 h) decline of TXNIP mRNA and protein. This decline correlated with accumulation of secreted insulin into the medium. Accordingly, exogenously added insulin reduced TXNIP mRNA and protein levels, an effect counteracted by the insulin/IGF-1 receptor antagonist linsitinib. The inhibition of PI3K and Akt/PKB increased TXNIP mRNA levels. The histone deacetylase (HDAC1/2/3) inhibitor MS-275 completely abrogated the time-dependent, insulin-mediated reduction of TXNIP, leaving the effect of palmitate unaltered. Acute stimulation of insulin secretion and chronic accentuation of cell death by palmitate occurred independently of TXNIP regulation. On the contrary, palmitate antagonized glucose-augmented ROS production. In conclusion, glucose-induced TXNIP expression is efficiently antagonized by two independent mechanisms, namely via an autocrine activation of insulin/IGF-1 receptors involving HDAC and by palmitate attenuating oxidative stress of β-cells.

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Thioredoxin interacting protein mediates lipid-induced impairment of glucose uptake in skeletal muscle

Cited by 19 publications

References 30 publications

RETRACTED: Icariin Ameliorates Palmitate-Induced Insulin Resistance Through Reducing Thioredoxin-Interacting Protein (TXNIP) and Suppressing ER Stress in C2C12 Myotubes

RETRACTED: Icariin Ameliorates Palmitate-Induced Insulin Resistance Through Reducing Thioredoxin-Interacting Protein (TXNIP) and Suppressing ER Stress in C2C12 Myotubes

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Palmitate and insulin counteract glucose-induced thioredoxin interacting protein (TXNIP) expression in insulin secreting cells via distinct mechanisms

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