Stearate‐Induced Apoptosis in Human Pancreatic β‐Cells is Associated with Changes in Membrane Protein Expression and These Changes are Inhibited by Oleate

Němcová‐Fürstová, Vlasta; Balušíková, Kamila; Halada, Petr; Pavlíková, Nela; Šrámek, Jiří; Kovář, Jan

doi:10.1002/prca.201800104

Cited by 8 publications

(6 citation statements)

References 57 publications

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“…Other molecules/events speculated to play a role in the mechanisms of FA-induced β-cell apoptosis include activation of transcription factor NF-κB (nuclear factor kappa B) [5,104,114,245,246], GPR120 [139], FAT/CD36 (fatty acid translocase/cluster of differentiation 36) [247], cathepsin D [208] and calpain-10 [248]; degradation of carboxypeptidase E [39]; cellular localization of annexin A2 and A4, reticulocalbin-2 and 14-3-3γ [249]; expression of Nck1 [250] and JunB downregulation [103].…”

Section: Other Mechanisms Involvedmentioning

confidence: 99%

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Šrámek

Němcová‐Fürstová

Kovář

2021

IJMS

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Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.

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Section: Other Mechanisms Involvedmentioning

confidence: 99%

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Šrámek

Němcová‐Fürstová

Kovář

2021

IJMS

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“…Meanwhile, a long-term high level of stearic acid exhibited a stronger destructive effect on β cells than that of palmitic acid [ 5 , 8 ]. Although endoplasmic reticulum (ER) stress [ 5 , 9 ] and apoptosis [ 8 , 10 ] are accepted as major contributors to stearic acid-induced β cell dysfunction, the molecular mechanisms involved in this remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

TCONS_00230836 silencing restores stearic acid-induced β cell dysfunction through alleviating endoplasmic reticulum stress rather than apoptosis

Guo

Zhang

et al. 2021

Genes Nutr

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Background Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic acid-stimulated lipotoxicity to β cells. Method Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA’s and candidate mRNAs’ levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. Results TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 significantly restored stearic acid-impaired glucose-stimulated insulin secretion through alleviating endoplasmic reticulum stress. However, stearic acid-induced β cell apoptosis was not obviously recovered. Conclusion Our findings suggest the involvement of TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.

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“…Next, we investigated whether stearate induced apoptosis like palmitate, as reported previously 12,14,16 . A ow cytometry analysis of Annexin V-positive cells showed that stearate increased apoptosis of OVCAR5 cells dose-dependently (Figs.…”

Section: Stearate Induces Apoptosis and Dna Damage In Ovarian Cancer ...mentioning

confidence: 77%

Stearate-rich diet and oleate restriction directly inhibit tumor growth via the unfolded protein response

Koji,

Jumpei,

Eijiro

et al. 2024

Preprint

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Fatty acids are known to have a significant impact on the properties of cancer cells. Therefore, Incorporating them into therapeutic strategies has been reported. However, few studies have examined the effects of individual fatty acids and their interaction in depth. The study analyzed the effects of various fatty acids on cancer cells and found that stearic acid, an abundant saturated fatty acid, had a stronger inhibitory effect on cell growth compared to palmitic acid, which is also an abundant saturated fatty acid, by inducing DNA damage and apoptosis through the unfolded protein response (UPR) pathway. Intriguingly, the negative effects of stearate were reduced by the presence of oleate, a different type of abundant fatty acid. In exploring the dietary impact on tumor growth, we combined a stearate-rich diet with the inhibition of stearoyl-CoA desaturase-1. This approach significantly reduced tumor growth in both ovarian cancer models and patient-derived xenografts (PDXs), including those with chemotherapy-resistant cases, by notably elevating stearate levels while reducing oleate levels within the tumors. Conversely, the negative effects of a stearate-rich diet were mitigated by an oleate-rich diet. The study shows that the dietary stearate can directly inhibit tumor growth through mechanisms involving DNA damage and apoptosis mediated by the UPR pathway. The results suggest that dietary interventions, which increase stearic acid levels while decreasing oleic acid levels, may be a promising therapeutic strategy in cancer treatment. This could lead to the development of new cancer treatment strategies.

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Stearate‐Induced Apoptosis in Human Pancreatic β‐Cells is Associated with Changes in Membrane Protein Expression and These Changes are Inhibited by Oleate

Cited by 8 publications

References 57 publications

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

TCONS_00230836 silencing restores stearic acid-induced β cell dysfunction through alleviating endoplasmic reticulum stress rather than apoptosis

Stearate-rich diet and oleate restriction directly inhibit tumor growth via the unfolded protein response

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