scholarly journals Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3017
Author(s):  
Jingya Lyu ◽  
Kensaku Fukunaga ◽  
Hitomi Imachi ◽  
Seisuke Sato ◽  
Toshihiro Kobayashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Oxidized Ldl ◽  
Specific Inhibitor ◽  
Density Lipoprotein ◽  
Dependent Manner ◽  
Cholesterol Accumulation ◽  
Impaired Insulin Secretion ◽  
Abca1 Expression ◽  
Impaired Insulin

Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.

scholarly journals The PI(4)P phosphatase Sac2 controls insulin granule docking and release

2019 ◽  
Vol 218 (11) ◽  
pp. 3714-3729 ◽  
Author(s):  
Phuoc My Nguyen ◽  
Nikhil R. Gandasi ◽  
Beichen Xie ◽  
Sari Sugahara ◽  
Yingke Xu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Membrane ◽  
Insulin Secretion ◽  
Dependent Manner ◽  
Impaired Insulin Secretion ◽  
Insulin Granules ◽  
Impaired Insulin ◽  
Insulin Granule ◽  
Phosphatidylinositol 4

Insulin granule biogenesis involves transport to, and stable docking at, the plasma membrane before priming and fusion. Defects in this pathway result in impaired insulin secretion and are a hallmark of type 2 diabetes. We now show that the phosphatidylinositol 4-phosphate phosphatase Sac2 localizes to insulin granules in a substrate-dependent manner and that loss of Sac2 results in impaired insulin secretion. Sac2 operates upstream of granule docking, since loss of Sac2 prevented granule tethering to the plasma membrane and resulted in both reduced granule density and number of exocytic events. Sac2 levels correlated positively with the number of docked granules and exocytic events in clonal β cells and with insulin secretion in human pancreatic islets, and Sac2 expression was reduced in islets from type 2 diabetic subjects. Taken together, we identified a phosphoinositide switch on the surface on insulin granules that is required for stable granule docking at the plasma membrane and impaired in human type 2 diabetes.

1516-P: A Comparison of the Contributions of Impaired Insulin Secretion and Insulin Resistance to the Development of Type 2 Diabetes in a Japanese Community: The Hisayama Study

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1516-P
Author(s):  
MASAHITO YOSHINARI ◽  
YOICHIRO HIRAKAWA ◽  
JUN HATA ◽  
MAYU HIGASHIOKA ◽  
TAKANORI HONDA ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

scholarly journals The Possible Mechanisms of the Impaired Insulin Secretion in Hypothyroid Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0131198 ◽  
Author(s):  
Aliashraf Godini ◽  
Asghar Ghasemi ◽  
Saleh Zahediasl
Keyword(s):  
Insulin Secretion ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

scholarly journals CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation

2016 ◽  
Vol 15 (3) ◽  
pp. e25-e27 ◽  
Author(s):  
Reuven Tsabari ◽  
Hila Iron Elyashar ◽  
Malena Cohen Cymberknowh ◽  
Oded Breuer ◽  
Shoshana Armoni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

scholarly journals Actin Polymerization in Macrophages in Response to Oxidized LDL and Apoptotic Cells: Role of 12/15-Lipoxygenase and Phosphoinositide 3-Kinase

2003 ◽  
Vol 14 (10) ◽  
pp. 4196-4206 ◽  
Author(s):  
Yury I. Miller ◽  
Dorothy S. Worrall ◽  
Colin D. Funk ◽  
James R. Feramisco ◽  
Joseph L. Witztum
Keyword(s):  
Cell Membrane ◽  
Actin Polymerization ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Specific Inhibitor ◽  
Density Lipoprotein ◽  
Oxidation Products ◽  
Apoptotic Cells ◽  
Lipid Oxidation Products ◽  
Phosphoinositide 3 Kinase

Formation of filamentous F-actin drives many cellular processes, including phagocytosis and cell spreading. We have recently reported that mouse macrophage 12/15-lipoxygenase (12/15-LO) activity promotes F-actin formation in filopodia during phagocytosis of apoptotic cells. Oxidized low-density lipoprotein (OxLDL) also stimulates robust F-actin formation and spreading of macrophages. However, unlike apoptotic cells, OxLDL did not cause specific translocation of 12/15-LO to the cell membrane, neither in macrophages nor in GFP-15LO–transfected COS-7 cells. Moreover, inhibition of 12/15-LO activity in macrophages by a specific inhibitor or by 12/15-LO gene disruption did not affect OxLDL-induced actin polymerization. Among LDL modifications modeling OxLDL, LDL modified by incubation with 15LO-overexpressing fibroblasts was as active in eliciting F-actin response as was OxLDL. This LDL modification is well known to produce minimally modified LDL (mmLDL), which is bioactive and carries lipid oxidation products similar to those produced by 12/15-LO catalysis. MmLDL activated phosphoinositide 3-kinase (PI3K), and PI3K inhibitors abolished mmLDL-induced macrophage spreading. We hypothesize that OxLDL and mmLDL may contribute oxidized lipids to the macrophage cell membrane and thereby mimic intracellular 12/15-LO activity, which leads to uncontrolled actin polymerization and dramatic cytoskeletal changes in macrophages.

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