scholarly journals Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic β-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression

2021 ◽  
Author(s):  
Huimin Lu ◽  
Rui Guo ◽  
Yunjin Zhang ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Stearic Acid ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Luciferase Reporter ◽  
Sequencing Analysis ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Shrna Expression ◽  
High Stearic Acid

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of lncRNA TCONS_00077866 (lnc866) in SA-induced β<i>-</i>cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-microRNA (miRNAs)-mRNA co-expression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β<i>-</i>cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.

scholarly journals Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic β-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression

2021 ◽  
Author(s):  
Huimin Lu ◽  
Rui Guo ◽  
Yunjin Zhang ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Stearic Acid ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Luciferase Reporter ◽  
Sequencing Analysis ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Shrna Expression ◽  
High Stearic Acid

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of lncRNA TCONS_00077866 (lnc866) in SA-induced β<i>-</i>cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-microRNA (miRNAs)-mRNA co-expression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β<i>-</i>cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.

scholarly journals Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic β-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression

2021 ◽  
Author(s):  
Huimin Lu ◽  
Rui Guo ◽  
Yunjin Zhang ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Stearic Acid ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Luciferase Reporter ◽  
Sequencing Analysis ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Shrna Expression ◽  
High Stearic Acid

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of lncRNA TCONS_00077866 (lnc866) in SA-induced β<i>-</i>cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-microRNA (miRNAs)-mRNA co-expression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β<i>-</i>cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.

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

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rui Guo ◽  
Yunjin Zhang ◽  
Yue Yu ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Endoplasmic Reticulum Stress ◽  
Stearic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Acid Diet ◽  
High Stearic Acid ◽  
Mouse Islets

Abstract 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.

scholarly journals TCONS_00230836 silencing restores stearic acid-induced β-cell dysfunction through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway rather than apoptosis

2020 ◽  
Author(s):  
Rui Guo ◽  
Yunjin Zhang ◽  
Yue Yu ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Stearic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Acid Diet ◽  
High Stearic Acid ◽  
Mouse Islets ◽  
Dependent Pathway

Abstract 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: The lncRNA 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 apparently restored stearic acid-impaired GSIS through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway. However, stearic acid-induced β-cell apoptosis was not obviously recovered. Conclusion: Our findings suggest the involvement of the lncRNA 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.

scholarly journals An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinyoung Kim ◽  
Kihyoun Park ◽  
Min Jung Kim ◽  
Hyejin Lim ◽  
Kook Hwan Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloid Accumulation ◽  
Human Diabetes

AbstractWe have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

scholarly journals Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

2021 ◽  
Vol 22 (15) ◽  
pp. 7917
Author(s):  
Hideaki Kaneto ◽  
Tomohiko Kimura ◽  
Masashi Shimoda ◽  
Atsushi Obata ◽  
Junpei Sanada ◽  
...  
Keyword(s):  
Large Scale ◽  
Cell Function ◽  
Apoptotic Cell ◽  
Early Stage ◽  
Insulin Biosynthesis ◽  
Protective Effects ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Toxicity

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

scholarly journals 5-Bromoprotocatechualdehyde Combats against Palmitate Toxicity by Inhibiting Parkin Degradation and Reducing ROS-Induced Mitochondrial Damage in Pancreatic β-Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 264
Author(s):  
Seon-Heui Cha ◽  
Chunying Zhang ◽  
Soo-Jin Heo ◽  
Hee-Sook Jun
Keyword(s):  
Cell Loss ◽  
Cellular Damage ◽  
Mitochondrial Morphology ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Zebrafish Model ◽  
Cell Dysfunction ◽  
Glucose Stimulated Insulin Secretion

Pancreatic β-cell loss is critical in diabetes pathogenesis. Up to now, no effective treatment has become available for β-cell loss. A polyphenol recently isolated from Polysiphonia japonica, 5-Bromoprotocatechualdehyde (BPCA), is considered as a potential compound for the protection of β-cells. In this study, we examined palmitate (PA)-induced lipotoxicity in Ins-1 cells to test the protective effects of BPCA on insulin-secreting β-cells. Our results demonstrated that BPCA can protect β-cells from PA-induced lipotoxicity by reducing cellular damage, preventing reactive oxygen species (ROS) overproduction, and enhancing glucose-stimulated insulin secretion (GSIS). BPCA also improved mitochondrial morphology by preserving parkin protein expression. Moreover, BPCA exhibited a protective effect against PA-induced β-cell dysfunction in vivo in a zebrafish model. Our results provide strong evidence that BPCA could be a potential therapeutic agent for the management of diabetes.

scholarly journals Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8016
Author(s):  
Tina Dahlby ◽  
Christian Simon ◽  
Marie Balslev Backe ◽  
Mattias Salling Dahllöf ◽  
Edward Holson ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Selective Inhibition ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Enhancer Of Zeste ◽  
Cell Gene Expression ◽  
Nfκb Pathway ◽  
Induced Apoptosis

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

scholarly journals EPC-Derived Exosomal miR-1246 and miR-1290 Regulate Phenotypic Changes of Fibroblasts to Endothelial Cells to Exert Protective Effects on Myocardial Infarction by Targeting ELF5 and SP1

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulang Huang ◽  
Lifang Chen ◽  
Zongming Feng ◽  
Weixin Chen ◽  
Shaodi Yan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Cardiac Injury ◽  
Immunofluorescence Staining ◽  
Luciferase Reporter ◽  
Protective Effects ◽  
Expression Levels ◽  
Phenotypic Changes

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Endothelial progenitor cell (EPC)-derived exosomes have been found to be effective in alleviating MI, while the detailed mechanisms remain unclear. The present study aimed to determine the protective effects of EPC-derived exosomal miR-1246 and miR-1290 on MI-induced injury and to explore the underlying molecular mechanisms. The exosomes were extracted from EPCs; gene expression levels were determined by quantitative real-time PCR, and protein expression levels were determined by western blot and immunofluorescence staining, respectively. The angiogenesis and proliferation of human cardiac fibroblasts (HCFs) were determined by tube formation assay and immunofluorescence staining of PKH67, respectively. Luciferase reporter, CHIP, and EMSA assays determined the interaction between miR-1246/1290 and the targeted genes (EFL5 and SP1). The protective effects of miR-1246/1290 on MI were evaluated in a rat model of MI. EPC-derived exosomes significantly upregulated miR-1246 and miR-1290 expression and promoted phenotypic changes of fibroblasts to endothelial cells, angiogenesis, and proliferation in HCFs. Exosomes from EPCs with miR-1246 or miR-1290 mimics transfection promoted phenotypic changes of fibroblasts to endothelial cells and angiogenesis in HCFs, while exosomes from EPCs with miR-1246 or miR-1290 knockdown showed opposite effects in HCFs. Mechanistically, miR-1246 and miR-1290 from EPC-derived exosomes induced upregulation of ELF5 and SP1, respectively, by targeting the promoter regions of corresponding genes. Overexpression of both ELF5 and SP1 enhanced phenotypic changes of fibroblasts to endothelial cells and angiogenesis in HCFs pretreated with exosomes from EPCs with miR-1246 or miR-1290 mimics transfection, while knockdown of both EFL5 and SP1 exerted the opposite effects in HCFs. Both ELF5 and SP1 can bind to the promoter of CD31, leading to the upregulation of CD31 in HCFs. Furthermore, in vivo animal studies showed that exosomes from EPCs with miR-1246 or miR-1290 overexpression attenuated the MI-induced cardiac injury in the rats and caused an increase in ELF5, SP1, and CD31 expression, respectively, but suppressed α-SMA expression in the cardiac tissues. In conclusion, our study revealed that miR-1246 and miR-1290 in EPC-derived exosomes enhanced in vitro and in vivo angiogenesis in MI, and these improvements may be associated with amelioration of cardiac injury and cardiac fibrosis after MI.

scholarly journals Overexpression of miR-297b-5p protects against stearic acid-induced pancreatic β-cell apoptosis by targeting LATS2

2020 ◽  
Vol 318 (3) ◽  
pp. E430-E439 ◽  
Author(s):  
Rui Guo ◽  
Yue Yu ◽  
Yunjin Zhang ◽  
Yinling Li ◽  
Xia Chu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Stearic Acid ◽  
Palmitic Acid ◽  
Cell Apoptosis ◽  
Control Group ◽  
Β Cell ◽  
Cell Dysfunction ◽  
High Stearic Acid ◽  
Mouse Islets

Chronic exposure to high concentrations of stearic acid (C18:0) can result in β -cell dysfunction, leading to development of type 2 diabetes. However, the molecular mechanisms underlying the destructive effects of stearic acid on β-cells remain largely unknown. In this study, we aimed to investigate the role of miR-297b-5p on stearic acid-induced β-cell apoptosis. Differential expression of microRNAs (miRNAs) was assessed in a β-TC6 cell line exposed to stearic acid, palmitic acid, or a normal culture medium by high-throughput sequencing. The apoptosis rate was measured by flow cytometry after miR-297b-5p mimic/inhibitor transfection, and large-tumor suppressor kinase 2 (LATS2) was identified as a target of miR-297b-5p using a luciferase activity assay. In vivo, C57BL/6 mice were fed with normal and high-stearic-acid diet, respectively. Mouse islets were used for similar identification of miR-297b-5p and Lats2 in β-TC6 cell. We selected two differentially expressed miRNAs in stearic acid compared with those in the palmitic acid and control groups. miR-297b-5p expression was significantly lower in β-TC6 cells and mouse islets in stearic acid than in control group. Upregulation of miR-297b-5p alleviated the stearic acid-induced cell apoptosis and reduction in insulin secretion by inhibiting Lats2 expression in vitro. Meanwhile, silencing Lats2 significantly reversed the stearic acid-stimulated β-cell dysfunction in both β-TC6 cells and islets. Our findings indicate a suppressive role for miR-297b-5p in stearic acid-induced β-cell apoptosis, which may reveal a potential target for the treatment of β-cell dysfunction in the pathogenesis of type 2 diabetes.

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