Fiber Specific Changes in Sphingolipid Metabolism in Skeletal Muscles of Hyperthyroid Rats

Chabowski, Adrian; Żendzian-Piotrowska, Małgorzata; Mikłosz, Agnieszka; Łukaszuk, Bartłomiej; Kurek, Krzysztof; Górski, Jan

doi:10.1007/s11745-013-3769-3

Cited by 8 publications

(7 citation statements)

References 39 publications

(49 reference statements)

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“…As previously reported by us [18,33] and others [1,34], prolonged thyroid hormone treatment caused only a small decrease in body weight (Table 1, -16%, P>0.05), but induced heart hypertrophy as indicated by either increased heart weight and/or size (compared to tibia, data not shown). Furthermore, plasma FFA, glucose and T 3 content was significantly increased (Table 1, 5-fold, +22% and 4,8-fold, P<0.05, respectively) after T 3 administration.…”

Section: Resultssupporting

confidence: 86%

“…In our study, CER accumulation in the heart of hyperthyroid rats is due to either acidic SMase activation or enhanced de novo sphingolipid synthesis. The main support for this hypothesis comes from studies in which plasma concentration of free fatty acids increases during hyperthyroidism [18,33] and as a consequence, their delivery to the heart also increases. This creates favorable conditions for increased ceramide synthesis, since it was shown that increased availability of extracellular palmitate was able to activate SPT-1, rate limiting enzyme for de novo synthesis of CER (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Ceramide is generated through de novo synthesis, salvage pathway (by ceramidases), and sphingomyelin cycle (by sphingomyelinases) (Fig. 1) [14,15,18]. The first and rate-limiting step of de novo process is catalyzed by the enzyme serine palmitoyltransferase (SPT), to form 3-ketosphinganine [12,13,19,20].…”

Section: Introductionmentioning

confidence: 99%

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Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Mikłosz

Łukaszuk

Chabowski

et al. 2015

Cell Physiol Biochem

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Background: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T₃) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T₃ treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), β-hydroxyacyl-CoA dehydrogenase (β-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). Conclusions: We conclude that prolonged T₃ treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Mikłosz

Łukaszuk

Chabowski

et al. 2015

Cell Physiol Biochem

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“…The first and rate-limiting step of de novo synthesis is the condensation of a fatty acyl-CoA, usually palmitoyl-CoA, with serine, which is catalyzed by the enzyme serine palmitoyltransferase (SPT), to form 3-ketosphinganine [ 1 , 2 , 8 ]. The final two steps of this pathway involve the generation of dihydroceramide from sphinganine (SFA) by the action of dihydroceramide synthase and its subsequent conversation into ceramide by dihydroceramide desaturase [ 2 , 9 , 10 ]. In addition, the ceramide can be further modified into alternative forms, including glucosylceramide and ceramide 1-phosphate, or converted into other metabolites such as sphingosine 1-phosphate [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Inhibition of Serine Palmitoyltransferase (SPT) and Sphingosine Kinase 1 (SphK1) on Palmitate Induced Insulin Resistance in L6 Myotubes

et al. 2013

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BackgroundThe objective of this study was to examine the effects of short (2 h) and prolonged (18 h) inhibition of serine palmitoyltransferase (SPT) and sphingosine kinase 1 (SphK1) on palmitate (PA) induced insulin resistance in L6 myotubes. MethodsL6 myotubes were treated simultaneously with either PA and myriocin (SPT inhibitor) or PA and Ski II (SphK1inhibitor) for different time periods (2 h and 18 h). Insulin stimulated glucose uptake was measured using radioactive isotope. Expression of insulin signaling proteins was determined using Western blot analyses. Intracellular sphingolipids content [sphinganine (SFA), ceramide (CER), sphingosine (SFO), sphingosine-1-phosphate (S1P)] were estimated by HPLC.ResultsOur results revealed that both short and prolonged time of inhibition of SPT by myriocin was sufficient to prevent ceramide accumulation and simultaneously reverse palmitate induced inhibition of insulin-stimulated glucose transport. In contrast, prolonged inhibition of SphK1 intensified the effect of PA on insulin-stimulated glucose uptake and attenuated further the activity of insulin signaling proteins (pGSK3β/GSK3β ratio) in L6 myotubes. These effects were related to the accumulation of sphingosine in palmitate treated myotubes. ConclusionMyriocin is more effective in restoration of palmitate induced insulin resistance in L6 myocytes, despite of the time of SPT inhibition, comparing to SKII (a specific SphK1 inhibitor). Observed changes in insulin signaling proteins were related to the content of specific sphingolipids, namely to the reduction of ceramide. Interestingly, inactivation of SphK1 augmented the effect of PA induced insulin resistance in L6 myotubes, which was associated with further inhibition of insulin stimulated PKB and GSK3β phosphorylation, glucose uptake and the accumulation of sphingosine.

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“…For the detection of protein content Western blotting procedures were applied as described previously (Chabowski et al, 2013;Lukaszuk et al, 2015;Miklosz et al, 2016). Briefly, the cells were lysed in ice-cold RIPA (radioimmunoprecipitation assay) buffer with protease and phosphatase inhibitors and sonicated for 1 min at 4°C.…”

Section: Protein Extraction and Western Blotmentioning

confidence: 99%

Challenging of AS160/TBC1D4 Alters Intracellular Lipid milieu in L6 Myotubes Incubated With Palmitate

Mikłosz

Łukaszuk

Żendzian-Piotrowska

et al. 2017

Journal Cellular Physiology

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The Akt substrate of 160 kDa (AS160) is a key regulator of GLUT4 translocation from intracellular depots to the plasma membrane in myocytes. Likely, AS160 also controls LCFAs transport, which requires relocation of fatty acid transporters. The aim of the present study was to determine the impact of AS160 knockdown on lipid milieu in L6 myotubes incubated with palmitate (PA). Therefore, we compared two different settings, namely: 1) AS160 knockdown prior to palmitate incubation (pre‐PA‐silencing, AS160−/PA); 2) palmitate incubation with subsequent AS160 knockdown (post‐PA‐silencing, PA/AS160−). The efficiency of AS160 silencing was checked at mRNA and protein levels. The expression and localization of FA transporters were determined using Western Blot and immunofluorescence analyses. Intracellular lipid content (FFA, DAG, TAG, and PL) and FA composition were estimated by GLC, whereas basal palmitate uptake was analyzed by means of scintigraphy. Both groups with silenced AS160 were characterized by a greater expression of FA transporters (FAT/CD36, FATP‐1, 4) which had contributed to an increased FA cellular influx. Accordingly, we observed that post‐PA‐silencing of AS160 resulted in a marked decrement in DAG, TAG, and PL contents, but increased FFA content (PA/AS160− vs. PA). The opposite effect was observed in the group with pre‐PA‐silencing of AS160 in which AS160 knockdown did not affect the lipid pools (AS160−/PA vs. PA). Our results indicate that post‐PA‐silencing of AS160 has a capacity to decrease the lipotoxic effect(s) of PA by decreasing the content of lipids (DAG and PL) that promote insulin resistance in myotubes. J. Cell. Physiol. 232: 2373–2386, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.

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Fiber Specific Changes in Sphingolipid Metabolism in Skeletal Muscles of Hyperthyroid Rats

Cited by 8 publications

References 39 publications

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Effects of Inhibition of Serine Palmitoyltransferase (SPT) and Sphingosine Kinase 1 (SphK1) on Palmitate Induced Insulin Resistance in L6 Myotubes

Challenging of AS160/TBC1D4 Alters Intracellular Lipid milieu in L6 Myotubes Incubated With Palmitate

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