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( Seung Lark Hwang ),( Ju Hye Yang ),( Yong Tae Jeong ),( Yong Deuk Kim ),( Xian Li ),( Yue Lu ),( Young Chae Chang ),( Kun Ho Chang ),( Kun Ho Son ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
The aim of the present study was to determine the effect of Tanshinone IIA (Tan IIA) on endoplasmic reticulum (ER) stress-induced insulinresistance in L6 myotubes and db/db mice. ER stress markers, RNA-activated protein kinase-like ER resident kinase (PERK), JNK, and AMPK activity were determined in tunicamycin-treated L6 myotubes. Insulin resistance was monitored using glucose uptake assays in vitro and blood glucose levels in vivo. Tan IIA clearly suppressed the phosphorylations of PERK and JNK and potentiated insulin-mediated Akt phosphorylation as well as glucose uptake via AMPK activation under ER stress. Furthermore, these effects are completely abrogated by siRNA-mediated knockdown of AMPK or LKB1. In addition, Tan IIA reduced blood glucose levels and body weights in db/db mice without altering food intake. These findings suggest that Tan IIA enhances insulin sensitivity and improves glucose metabolic disorders by increasing AMPK activity and attenuating ERstress-induced insulin resistance. ⓒ2012 Elsevier lnc. All rights reserved.
( Seung Lark Hwang ),( Yong Tae Jeong ),( Xian Li ),( Yong Deuk Kim ),( Yue Lu ),( Young Chae Chang ),( In Kyu Lee ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
BACKGROUND AND PURPOSE: Endoplasmic reticulum (ER) stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal-regulated kinase (ERK) antagonist is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin-treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells. EXPERIMENTAL APPROACH: ER stress was induced in L6 myotubes using tunicamycin (5 μg·mL(-1) ) or thapsigargin (300 nM) and cells were transfected with siRNA ERK or AMPKα2. Changes in ER stress and in the ERK and AMPK signalling pathways were explored by Western blotting. The phosphorylation levels of insulin receptor substrate 1 were analysed by immunoprecipitation and using glucose uptake assay. KEY RESULTS: ER stress dampened insulin-stimulated signals and glucose uptake, whereas treatment with the specific ERK inhibitor U0126 (25 μM) rescued impaired insulin signalling via AMPK activation. In db/db mice, U0126 administration decreased markers of insulin resistance and increased the phosphorylations of Akt and AMPK in muscle tissues. CONCLUSIONS AND IMPLICATIONS: Inhibition of ERK signalling pathways by a chemical inhibitor and knockdown of ERK improved AMPK and Akt signallings and reversed ER stress-induced insulin resistance in L6 myotubes. These findings suggest that ERK signalling plays an important role in the regulation of insulin signals in muscle cells under ER stress. Abbreviations: ACC, acetyl-CoA carboxylase; Ad-DN-AMPK adenovirus dominat negative; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; PERK, RNA-activated protein kinase-like ER resident kinase; IRE-1, inositol-requiring kinase-;siRNA, small interfering RNA; UPR, unfolded protein; IRS-1, insulin receptor substrate-1; WT, wild type
( Seung Lark Hwang ),( Xian Li ),( Yue Lu ),( Ye Jin ),( Yong Tae Jeong ),( Yong Deuk Kim ),( In Kyu Lee ),( Yoshitaka Taketomi ),( Hiroyasu Sato ),( You Sook Cho ),( Makoto Murakami ),( Hyeun Wook Ch 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Background: Aggregation of FcεRI activates a cascade of signaling events leading to mast cell activation, followed by inhibitory signals that turn off the activating signals. However, the overall view of negative signals in mast cells is still incomplete. Although AMP-activated protein kinase (AMPK), which is generally known as a regulator of energy metabolism, is also associated with anti-inflammation, little is known about the role of AMPK in mast cells. Objectives: We investigated the role of AMPK and its regulatory mechanism in mast cells. Method: The roles of AMPK in FcεRI-dependent activation of bone marrow-derived mast cells (BMMCs) were evaluated by using chemical agents, small interfering RNAs (siRNAs), or adenovirus that modulated the activity or expression of AMPK signaling components. In addition, AMPKα2(-/-) mice were used to verify the role of AMPK in anaphylactic models. Results: FcεRI signaling and associated effector functions in BMMCs were suppressed by the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and were conversely augmented by siRNA knockdown of AMPKα2 or liver kinase B1 (LKB1), an upstream kinase of AMPK. Furthermore, AMPKα2 deficiency led to increased FcεRI-mediated BMMC activation and anaphylaxis that were insensitive to AICAR, whereas enforced expression of AMPKα2 in AMPKα2(-/-) BMMCs reversed the hypersensitive FcεRI signaling to normal levels. Pharmacologic inhibition or siRNA knockdown of Fyn mimicked AMPK activation, suggesting that Fyn counterregulates the LKB1-AMPK axis. Mechanistically, Fyn controlled AMPK activity by regulating LKB1 localization. Conclusions: The Fyn-regulated LKB1-AMPK axis acts as a novel inhibitory module for mast cell activation, which points to AMPK activators as therapeutic drugs for allergic diseases. (J Allergy Chin Immunol 2013;132: 729-36)
( Seung Lark Hwang ),( Yue Lu ),( Xian Li Msc ),( Yong Deuk Kim ),( You Sook Cho ),( Yurn Dong Jahng ),( Jong Keun Son ),( Youn Ju Lee ),( Won Ku Kang ),( Yoshitaka Taketomi ),( Makoto Murakami ),( Ta 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells. Objective: We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis. Methods: Wild-type or AMPKa22/2 mice, or bone marrow. derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK in FcεRI-dependent signaling. Results: The ERK1/2 pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside similarly inhibited FcεRI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK1/2-specific small interfering RNA also mimicked this effect on FcεRI signals. Moreover, AMPKa2 knockdown or deficiency led to increased FcεRI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside, suggesting that the suppression of FcεRI signals by the inhibition of the ERK1/2 pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by regulating its subcellular translocation. Conclusions: ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby activating FcεRI signals in mast cells. (J Allergy Clin Immunol 2014;134:714-21.)
Seung-Lark Hwang,Okyun Kwon,Sun-Gyun Kim,이인규,김영덕 생화학분자생물학회 2013 Experimental and molecular medicine Vol.45 No.5
Glucagon-like peptide-1 (GLP-1) is a potent glucoincretin hormone and an important agent for the treatment of type 2 diabetes. Here we demonstrate that B-cell translocation gene 2 (BTG2) is a crucial regulator in GLP-1-induced insulin gene expression and insulin secretion via upregulation of pancreatic duodenal homeobox-1 (PDX-1) in pancreatic b-cells. GLP-1 treatment significantly increased BTG2, PDX-1 and insulin gene expression in pancreatic b-cells. Notably, adenovirus-mediated overexpression of BTG2 significantly elevated insulin secretion, as well as insulin and PDX-1 gene expression. Physical interaction studies showed that BTG2 is associated with increased PDX-1 occupancy on the insulin gene promoter via a direct interaction with PDX-1. Exendin-4 (Ex-4), a GLP-1 agonist, and GLP-1 in pancreatic b-cells increased insulin secretion through the BTG2–PDX-1–insulin pathway, which was blocked by endogenous BTG2 knockdown using a BTG2 small interfering RNA knockdown system. Finally, we revealed that Ex-4 and GLP-1 significantly elevated insulin secretion via upregulation of the BTG2–PDX-1 axis in pancreatic islets, and this phenomenon was abolished by endogenous BTG2 knockdown. Collectively, our current study provides a novel molecular mechanism by which GLP-1 positively regulates insulin gene expression via BTG2,suggesting that BTG2 has a key function in insulin secretion in pancreatic b-cells.
( Seung Lark Hwang ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
The aim of this study was to elucidate the effects of natural vanadium-containing Jeju ground water on glucose uptake in L6 myotubes and adipogensesis in 3T3 L1 cells. The Jeju ground water samplescontaining vanadium components were designated as S1 (8.0 ± 0.9 μg/l), S2 (24.0 ± 2.0 μg/l), and S3 (26.0 ± 2.0 μg/l), respectively. To investigate the effects of the Jeju ground water on glucose uptake in L6 myotubes, L6 cells were differentiated in media containing deionized distilled water (DDW group) and the water samples (S1, S2, and S3 groups). After daily changes in cultured media containing theJeju ground water samples for 1 week, all samples had increased glucose uptake compared to the DDW group and the order of glucose uptake increased in parallel with vanadium content (S3 > S2 > S1). In addition, S3 significantly stimulated the phosphorylation of the Thr-172 residue of the AMP-activated protein kinase-α subunit and the Ser-79 subunit of acetyl-CoA carboxylase compared to the DDW group. The effect of glucose uptake by S3 was reversed by pretreatment with Compound C, an AMPK inhibitor. Interestingly, vanadium pentoxide also increased glucose uptake and activated AMPK activity in a dose-dependent manner. Furthermore, as compared to the DDW treated group, S3 treatment inhibited adipogenesis of 3T3-L1 cells by down regulation of expressions of adipogenic transcription factors. Taken together, these findings suggest that S3 displays beneficial effects in the treatment of diabetes, at least in part through the activation of AMPK activity.
Pinusolide improves high glucose-insulin resistance via activation of AMP-activated protein kinase
( Seung Lark Hwang ),( Yong Tae Jeong ),( Ju Hye Yang ),( Xian Li ),( Yue Lu ),( Jong Keun Son ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in the maintenance of cellular energy homeostasis, and several natural compounds that activate AMPK possibly enhance glucose uptake by muscle cells. In this study, we found that pinusolide stimulated AMPK phosphorylation and glucose uptake and these effects were significantly reduced by siRNA LKB1 or compound C, suggesting that enhanced glucose uptake by pinusolide is predominantly accomplished via an LKB1-mediated AMPK activation pathway. An insulin resistance state was induced by exposing cells to 30mM glucose, as indicated by reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake. Under these conditions, the phosphorylation of AMPK and ACC were decreased. Surprisingly, disruptedinsulin signaling and decreased AMPK activity by high glucose concentrations were prevented by pinusolide. Moreover, this treatment increased insulin-stimulated glucose uptake via AMPK activation. Taken together, our findings suggest a link between high glucose and insulin resistance in muscle cells, and provide further evidence that pinusolide attenuates blockade of insulin signaling by enhancing IRS-1 tyrosine phosphorylation by the activating the AMPK pathway. In addition, this study indicates the targeting of AMPK represents a new therapeutic strategy for hyperglycemia-inducedinsulin resistance and type 2 diabetes.Crown Copyright ⓒ2013 Published by Elsevier Ine. All rights reserved.
Hwang, Seung-Lark,Li, Xian,Lu, Yue,Jin, Ye,Jeong, Yong-Tae,Kim, Yong Deuk,Lee, In-Kyu,Taketomi, Yoshitaka,Sato, Hiroyasu,Cho, You Sook,Murakami, Makoto,Chang, Hyeun Wook Elsevier 2013 The Journal of allergy and clinical immunology Vol.132 No.3
<P><B>Background</B></P> <P>Aggregation of FcεRI activates a cascade of signaling events leading to mast cell activation, followed by inhibitory signals that turn off the activating signals. However, the overall view of negative signals in mast cells is still incomplete. Although AMP-activated protein kinase (AMPK), which is generally known as a regulator of energy metabolism, is also associated with anti-inflammation, little is known about the role of AMPK in mast cells.</P> <P><B>Objectives</B></P> <P>We investigated the role of AMPK and its regulatory mechanism in mast cells.</P> <P><B>Method</B></P> <P>The roles of AMPK in FcεRI-dependent activation of bone marrow–derived mast cells (BMMCs) were evaluated by using chemical agents, small interfering RNAs (siRNAs), or adenovirus that modulated the activity or expression of AMPK signaling components. In addition, <I>AMPKα2</I> <SUP>−/−</SUP> mice were used to verify the role of AMPK in anaphylactic models.</P> <P><B>Results</B></P> <P>FcεRI signaling and associated effector functions in BMMCs were suppressed by the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and were conversely augmented by siRNA knockdown of AMPKα2 or liver kinase B1 (LKB1), an upstream kinase of AMPK. Furthermore, <I>AMPKα2</I> deficiency led to increased FcεRI-mediated BMMC activation and anaphylaxis that were insensitive to AICAR, whereas enforced expression of AMPKα2 in <I>AMPKα2</I> <SUP>−/−</SUP> BMMCs reversed the hypersensitive FcεRI signaling to normal levels. Pharmacologic inhibition or siRNA knockdown of Fyn mimicked AMPK activation, suggesting that Fyn counterregulates the LKB1-AMPK axis. Mechanistically, Fyn controlled AMPK activity by regulating LKB1 localization.</P> <P><B>Conclusions</B></P> <P>The Fyn-regulated LKB1-AMPK axis acts as a novel inhibitory module for mast cell activation, which points to AMPK activators as therapeutic drugs for allergic diseases.</P>