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Michael P Czech - One of the best experts on this subject based on the ideXlab platform.
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immunotherapy for infarcts in vivo postinfarction macrophage modulation using intramyocardial microparticle delivery of MAP4K4 small interfering rna
2020Co-Authors: Jun Luo, Myriam Aouadi, Michael P Czech, Matthew S Weaver, Timothy P Fitzgibbons, Margaret D AllenAbstract:The myeloid cells infiltrating the heart early after acute myocardial infarction elaborate a secretome that largely orchestrates subsequent ventricular wall repair. Regulating this innate immune response could be a means to improve infarct healing. To pilot this concept, we utilized (β1,3-d-) glucan-encapsulated small interfering RNA (siRNA)-containing particles (GeRPs), targeting mononuclear phagocytes, delivered to mice as a one-time intramyocardial injection immediately after acute infarction. Findings demonstrated that cardiac macrophages phagocytosed GeRPs in vivo and had little systemic dissemination, thus providing a means to deliver local therapeutics. Acute infarcts were then injected in vivo with phosphate-buffered saline (PBS; vehicle) or GeRPs loaded with siRNA to MAP4K4, and excised hearts were examined at 3 and 7 days by quantitative polymerase chain reaction, flow cytometry, and histology. Compared with infarcted PBS-treated hearts, hearts with intrainfarct injections of siRNA-loaded GeRPs exhibited 69-89% reductions in transcripts for MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4), interleukin (IL)-1β, and tumor necrosis factor α at 3 days. Expression of other factors relevant to matrix remodeling-monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases, hyaluronan synthases, matricellular proteins, and profibrotic factors transforming growth factor beta (TGF-β), and connective tissue growth factor (CTGF)-were also decreased. Most effects peaked at 3 days, but, in some instances (MAP4K4, IL-1β, TGF-β, CTGF, versican, and periostin), suppression persisted to 7 days. Thus, direct intramyocardial GeRP injection could serve as a novel and clinically translatable platform for in vivo RNA delivery to intracardiac macrophages for local and selective immunomodulation of the infarct microenvironment.
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MAP4K4 signaling nodes in metabolic and cardiovascular diseases
2016Co-Authors: Joseph V Virbasius, Michael P CzechAbstract:Mitogen-activated kinase kinase kinase kinase 4 (MAP4K4), originally identified in small interfering (si)RNA screens and characterized by tissue-specific gene deletions, is emerging as a regulator of glucose homeostasis and cardiovascular health. Recent studies have shown that MAP4K4 gene ablation or inhibition of its kinase activity attenuates hyperglycemia and plaque formation in mouse models of insulin resistance and atherosclerosis, and suggest roles for MAP4K4 in multiple signaling systems, including NFκB activation, small GTPase regulation, the Hippo cascade, and regulation of cell dynamics by FERM domain proteins. This new and promising area of inquiry raises key questions that need to be addressed, such as defining which of the above or other effectors mediate MAP4K4 control of metabolic and vascular functions, and identifying upstream activators of MAP4K4.
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inducible deletion of protein kinase MAP4K4 in obese mice improves insulin sensitivity in liver and adipose tissues
2015Co-Authors: Laura V Danai, Rachel Roth J Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K Kim, Michael P CzechAbstract:Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) attenuates insulin signaling, but confirmation in vivo is lacking since MAP4K4 knockout is lethal during embryogenesis. We thus generated mice with floxed MAP4K4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body MAP4K4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced MAP4K4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional MAP4K4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with MAP4K4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) MAP4K4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) MAP4K4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.
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MAP4K4 suppresses srebp 1 and adipocyte lipogenesis independent of jnk signaling
2013Co-Authors: Laura V Danai, Kalyani V P Guntur, Adilson L Guilherme, Juerg R Straubhaar, Sarah M Nicoloro, Michael P CzechAbstract:Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for MAP4K4 as a suppressor of lipid synthesis. We further report here the surprising finding that MAP4K4 suppresses adipocyte lipogenesis independently of JNK. Thus, while MAP4K4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of 14C-glucose and 14C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of MAP4K4 fails to activate endogenous JNK, while MAP4K4 depletion does not attenuate JNK activation by tumor necrosis factor α. MAP4K4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with MAP4K4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show MAP4K4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that MAP4K4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that MAP4K4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.
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identification of MAP4K4 as a novel suppressor of skeletal muscle differentiation
2013Co-Authors: Mengxi Wang, Shinya U Amano, Rachel Roth J Flach, Anil Chawla, Myriam Aouadi, Michael P CzechAbstract:Myoblast differentiation into mature myotubes is a critical step in the development and repair of human skeletal muscle. Here we show that small interfering RNA (siRNA)-based silencing of the Ste20-like mitogen-activated protein 4 kinase 4 (MAP4K4) in C2C12 myoblasts markedly enhances expression of myogenic differentiation genes, myoblast fusion, and myotube diameter. In contrast, adenovirus-mediated expression of native MAP4K4 in C2C12 cells attenuates each of these processes, indicating that MAP4K4 is a negative regulator of myogenic differentiation and hypertrophy. Expression of a MAP4K4 kinase-inactive mutant enhances myotube formation, suggesting that the kinase activity of MAP4K4 is essential for its inhibition of muscle differentiation. MAP4K4 regulation of myogenesis is unlikely to be mediated by classic mitogen-activated protein kinase (MAPK) signaling pathways, because no significant difference in phosphorylation of extracellular signal-regulated kinase (ERK), p38, or c-Jun N-terminal kinase (JNK) is observed in MAP4K4-silenced cells. Furthermore, silencing of these other MAPKs does not result in a hypertrophic myotube phenotype like that seen with MAP4K4 depletion. Uniquely, MAP4K4 silencing upregulates the expression of the myogenic regulatory factor Myf5, whose depletion inhibits myogenesis. Furthermore, Myf5 is required for enhancement of myotube formation in MAP4K4-silenced cells, while Myf5 overexpression rescues MAP4K4-mediated inhibition of myogenic differentiation. These results demonstrate that MAP4K4 is a novel suppressor of skeletal muscle differentiation, acting through a Myf5-dependent mechanism.
Tsehua Tan - One of the best experts on this subject based on the ideXlab platform.
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rbm4a srsf3 MAP4K4 splicing cascade constitutes a molecular mechanism for regulating brown adipogenesis
2018Co-Authors: Hui Yu Peng, Tsehua Tan, Yu Chih Liang, Huai Chia Chuang, Ying Ju Lin, Jung Chun LinAbstract:An increase in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) reportedly attenuates insulin-mediated signaling which participates in the development of brown adipose tissues (BATs). Nevertheless, the effect of MAP4K4 on brown adipogenesis remains largely uncharacterized. In this study, results of a transcriptome analysis (also referred as RNA-sequencing) showed differential expressions of MAP4K4 or SRSF3 transcripts isolated from distinct stages of embryonic BATs. The discriminative splicing profiles of MAP4K4 or SRSF3 were noted as well in brown adipocytes (BAs) with RNA-binding motif protein 4-knockout (RBM4−/−) compared to the wild-type counterparts. Moreover, the relatively high expressions of authentic SRSF3 transcripts encoding the splicing factor functioned as a novel regulator toward MAP4K4 splicing during brown adipogenesis. The presence of alternatively spliced MAP4K4 variants exerted differential effects on the phosphorylation of c-Jun N-terminal protein kinase (JNK) which was correlated with the differentiation or metabolic signature of BAs. Collectively, the RBM4-SRSF3-MAP4K4 splicing cascade constitutes a novel molecular mechanism in manipulating the development of BAs through related signaling pathways.
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rbm4 srsf3 MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell
2018Co-Authors: Jung Chun Lin, Tsehua Tan, Yu Chih Liang, Huai Chia Chuang, Yuan Chii Lee, Yang C Fann, Kory R Johnson, Ying Ju LinAbstract:Abstract Alternative splicing (AS) of pre-messenger (m)RNA is a pivotal mechanism in expanding proteomic diversity, which determines the functions of mammalian cells. By conducting transcriptome analyses to profile splicing events in human colorectal cancer (CRC) tissues compared to adjacent normal counterparts, we noted differential splicing profiles of serine/arginine-rich splicing factor 3 (SRSF3) and mitogen-activated protein 4 kinase 4 (MAP4K4) in cancerous tissues of CRC compared to adjacent normal tissues. In addition to SRSF3-mediated autoregulation, RNA-binding motif protein 4 (RBM4) constituted another mechanism in reprogramming the splicing profile of SRSF3. Upregulated expressions of SRSF3 in CRC cells modulated utilization of MAP4K4 exon 16 in a sequence-dependent manner. Alternatively spliced MAP4K4 variants exhibited differential effects on the phosphorylation of c-Jun N-terminal protein kinase 1 (JNK1) which subsequently modulated expression profiles of E-cadherin, N-cadherin, and vimentin, all of which are involved in the migration and invasion of CRC cells. Collectively, RBM4-SRSF3-MAP4K4 constitutes a novel mechanism for manipulating the metastasis of CRC cells through the JNK1 signaling pathway.
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MAP4K4 and il 6 th17 cells play important roles in non obese type 2 diabetes
2017Co-Authors: Huai Chia Chuang, Tsehua TanAbstract:Obesity is a causal factor of type 2 diabetes (T2D); however, people without obesity (including lean, normal weight, or overweight) may still develop T2D. Non-obese T2D is prevalent in Asia and also frequently occurs in Europe. Recently, multiple evidences oppose the notion that either obesity or central obesity (visceral fat accumulation) promotes non-obese T2D. Several factors such as inflammation and environmental factors contribute to non-obese T2D. According to the data derived from gene knockout mice and T2D clinical samples in Asia and Europe, the pathogenesis of non-obese T2D has been unveiled recently. MAP4K4 downregulation in T cells results in enhancement of the IL-6+ Th17 cell population, leading to insulin resistance and T2D in both human and mice. Moreover, MAP4K4 single nucleotide polymorphisms and epigenetic changes are associated with T2D patients. Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. Future investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D.
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expression of MAP4K4 is associated with worse prognosis in patients with stage ii pancreatic ductal adenocarcinoma
2008Co-Authors: John J Liang, Tsehua Tan, Hua Wang, Asif Rashid, Rosa F Hwang, Stanley R Hamilton, James L Abbruzzese, Douglas B Evans, Huamin WangAbstract:Purpose: Mitogen-activated protein 4 kinase 4 (MAP4K4) is a serine/threonine kinase and belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is overexpressed in many types of human cancer and cancer cell lines. MAP4K4 plays an important role in transformation, invasiveness, adhesion, and cell migration. However, the expression of MAP4K4 and its significance in pancreatic ductal adenocarcinoma (PDA) has not been studied. Experimental Design: We examined the expression of MAP4K4 by immunohistochemistry using tissue microarrays consisting of 66 stage II PDA and their paired benign pancreatic tissue. The staining results were categorized as MAP4K4-H or MAP4K4-L. The results were correlated with clinicopathologic features and patient survival. Results: MAP4K4 was overexpressed (MAP4K4-H) in 30 of 66 (46%) PDAs and was higher than the paired benign pancreatic tissue samples (19%; P = 0.002). The median overall and recurrence-free survival for patients with MAP4K4-H PDAs were 19.5 and 9.3 months, respectively, compared with 65.2 and 28.8 months for patients with MAP4K4-L tumor ( P = 0.02 and 0.0005, log-rank test). MAP4K4 expression was associated with poor overall and recurrence-free survival in univariate analysis ( P = 0.02 and 0.001). In multivariate analysis, MAP4K4 expression significantly correlated with overall and recurrence-free survival ( P = 0.025 and 0.004) independent of age, tumor size, differentiation, and stage. MAP4K4 expression was also associated with higher frequency of recurrence/metastasis, larger tumor size, and increased number of positive lymph nodes ( P < 0.05). Conclusion: MAP4K4 was overexpressed in about half of PDAs. Overexpression of MAP4K4 was associated with worse prognosis and is a prognostic marker for stage II PDAs.
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tumorigenesis suppressor pdcd4 down regulates mitogen activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion
2006Co-Authors: Hsinsheng Yang, Connie P Matthews, Timothy Clair, Qing Wang, Alyson R Baker, Tsehua Tan, Nancy H ColburnAbstract:Programmed cell death 4 (Pdcd4) suppresses neoplastic transformation by inhibiting the activation of c-Jun and consequently AP-1-dependent transcription. We report that Pdcd4 blocks c-Jun activation by inhibiting the expression of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1)/hematopoietic progenitor kinase 1, a kinase upstream of Jun N-terminal kinase (JNK). cDNA microarray analysis of Pdcd4-overexpressing RKO human colon carcinoma cells revealed MAP4K1 as the sole target of Pdcd4 on the JNK activation pathway. Cotransfection of a MAP4K1 promoter-reporter with Pdcd4 demonstrated inhibition of transcription from the MAP4K1 promoter. Ectopic expression of Pdcd4 in metastatic RKO cells suppressed invasion. MAP4K1 activity is functionally significant in invasion, as overexpression of a dominant negative MAP4K1 (dnMAP4K1) mutant in RKO cells inhibited not only c-Jun activation but also invasion. Overexpression of a MAP4K1 cDNA in Pdcd4-transfected cells rescued the kinase activity of JNK. Thus, Pdcd4 suppresses tumor progression in human colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription.
Rachel Roth J Flach - One of the best experts on this subject based on the ideXlab platform.
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protein kinase mitogen activated protein kinase kinase kinase kinase 4 MAP4K4 promotes obesity induced hyperinsulinemia
2016Co-Authors: Rachel Roth J Flach, Laura V Danai, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Marina T Distefano, Mark J S Kelly, Agata Jurczyk, Rohit Sharma, Jason K KimAbstract:Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of MAP4K4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body MAP4K4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo. After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase MAP4K4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice.
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endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
2015Co-Authors: Rachel Roth J Flach, Samit Kumar Bhattacharya, Myriam Aouadi, Laura V Danai, Athanasia Skoura, Anouch Matevossian, Wei Zheng, Christian Cortes, Nana Hagan, Joseph C YaweAbstract:Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis.
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inducible deletion of protein kinase MAP4K4 in obese mice improves insulin sensitivity in liver and adipose tissues
2015Co-Authors: Laura V Danai, Rachel Roth J Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K Kim, Michael P CzechAbstract:Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) attenuates insulin signaling, but confirmation in vivo is lacking since MAP4K4 knockout is lethal during embryogenesis. We thus generated mice with floxed MAP4K4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body MAP4K4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced MAP4K4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional MAP4K4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with MAP4K4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) MAP4K4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) MAP4K4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.
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identification of MAP4K4 as a novel suppressor of skeletal muscle differentiation
2013Co-Authors: Mengxi Wang, Shinya U Amano, Rachel Roth J Flach, Anil Chawla, Myriam Aouadi, Michael P CzechAbstract:Myoblast differentiation into mature myotubes is a critical step in the development and repair of human skeletal muscle. Here we show that small interfering RNA (siRNA)-based silencing of the Ste20-like mitogen-activated protein 4 kinase 4 (MAP4K4) in C2C12 myoblasts markedly enhances expression of myogenic differentiation genes, myoblast fusion, and myotube diameter. In contrast, adenovirus-mediated expression of native MAP4K4 in C2C12 cells attenuates each of these processes, indicating that MAP4K4 is a negative regulator of myogenic differentiation and hypertrophy. Expression of a MAP4K4 kinase-inactive mutant enhances myotube formation, suggesting that the kinase activity of MAP4K4 is essential for its inhibition of muscle differentiation. MAP4K4 regulation of myogenesis is unlikely to be mediated by classic mitogen-activated protein kinase (MAPK) signaling pathways, because no significant difference in phosphorylation of extracellular signal-regulated kinase (ERK), p38, or c-Jun N-terminal kinase (JNK) is observed in MAP4K4-silenced cells. Furthermore, silencing of these other MAPKs does not result in a hypertrophic myotube phenotype like that seen with MAP4K4 depletion. Uniquely, MAP4K4 silencing upregulates the expression of the myogenic regulatory factor Myf5, whose depletion inhibits myogenesis. Furthermore, Myf5 is required for enhancement of myotube formation in MAP4K4-silenced cells, while Myf5 overexpression rescues MAP4K4-mediated inhibition of myogenic differentiation. These results demonstrate that MAP4K4 is a novel suppressor of skeletal muscle differentiation, acting through a Myf5-dependent mechanism.
Laura V Danai - One of the best experts on this subject based on the ideXlab platform.
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protein kinase mitogen activated protein kinase kinase kinase kinase 4 MAP4K4 promotes obesity induced hyperinsulinemia
2016Co-Authors: Rachel Roth J Flach, Laura V Danai, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Marina T Distefano, Mark J S Kelly, Agata Jurczyk, Rohit Sharma, Jason K KimAbstract:Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of MAP4K4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body MAP4K4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo. After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase MAP4K4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice.
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endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
2015Co-Authors: Rachel Roth J Flach, Samit Kumar Bhattacharya, Myriam Aouadi, Laura V Danai, Athanasia Skoura, Anouch Matevossian, Wei Zheng, Christian Cortes, Nana Hagan, Joseph C YaweAbstract:Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis.
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inducible deletion of protein kinase MAP4K4 in obese mice improves insulin sensitivity in liver and adipose tissues
2015Co-Authors: Laura V Danai, Rachel Roth J Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K Kim, Michael P CzechAbstract:Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) attenuates insulin signaling, but confirmation in vivo is lacking since MAP4K4 knockout is lethal during embryogenesis. We thus generated mice with floxed MAP4K4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body MAP4K4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced MAP4K4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional MAP4K4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with MAP4K4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) MAP4K4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) MAP4K4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.
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role of protein kinase MAP4K4 in energy metabolism a dissertation
2015Co-Authors: Laura V DanaiAbstract:Systemic glucose regulation is essential for human survival as low or chronically high glucose levels can be detrimental to the health of an individual. Glucose levels are highly regulated via inter-organ communication networks that alter metabolic function to maintain euglycemia. For example, when nutrient levels are low, pancreatic α-cells secrete glucagon, which signals to the liver to promote glycogen breakdown and glucose production. In times of excess nutrient intake, pancreatic β-cells release insulin. Insulin signals to the liver to suppress hepatic glucose production, and signals to the adipose tissue and the skeletal muscle to take up excess glucose via insulin-regulated glucose transporters. Defects in this inter-organ communication network including insulin resistance can result in glucose deregulation and ultimately the onset of type-2 diabetes (T2D). To identify novel regulators of insulin-mediated glucose transport, our laboratory performed an siRNA-mediated gene-silencing screen in cultured adipocytes and measured insulin-mediated glucose transport. Gene silencing of Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a Sterile-20-related serine/threonine protein kinase, enhanced insulin-stimulated glucose transport, suggesting MAP4K4 inhibits insulin action and glucose transport. Thus, for the first part of my thesis, I explore the role of MAP4K4 in cultured adipose cells and show that MAP4K4 also represses lipid synthesis independent of its effects on glucose transport. MAP4K4 inhibits lipid synthesis in a Mechanistic target of rapamycin complex 1 (mTORC1)- and Sterol regulatory element-binding transcription factor 1 (Srebp-1)-dependent mechanism and not via a c-Jun NH2-terminal kinase (Jnk)-dependent mechanism. For the second part of my thesis, I explore the metabolic function of MAP4K4 in vivo. Using mice with loxP sites flanking the MAP4K4 allele and a ubiquitously expressed tamoxifen-activated Cre, we inducibly ablated MAP4K4 expression in adult mice and found significant improvements in metabolic health indicated by improved fasting glucose and whole-body insulin action. To assess the role of MAP4K4 in specific metabolic tissues responsible for systemic glucose regulation, we employed tissue-specific knockout mice to deplete MAP4K4 in adipose tissue using an adiponectin-cre transgene, liver using an albumin-cre transgene, and skeletal muscle using a Myf5-cre transgene. Ablation of MAP4K4 expression in adipose tissue or liver had no impact on whole body glucose homeostasis or insulin resistance. However, we surprisingly found that MAP4K4 depletion in Myf5-positive tissues, which include skeletal muscles, largely recapitulates the metabolic phenotypes observed in systemic MAP4K4 knockout mice, restoring obesity-induced glucose intolerance and insulin resistance. Furthermore these metabolic changes were associated with enhanced insulin signaling to Akt in the visceral adipose tissue, a tissue that is nearly devoid of Myf5-positive cells and does not display changes in…
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MAP4K4 suppresses srebp 1 and adipocyte lipogenesis independent of jnk signaling
2013Co-Authors: Laura V Danai, Kalyani V P Guntur, Adilson L Guilherme, Juerg R Straubhaar, Sarah M Nicoloro, Michael P CzechAbstract:Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for MAP4K4 as a suppressor of lipid synthesis. We further report here the surprising finding that MAP4K4 suppresses adipocyte lipogenesis independently of JNK. Thus, while MAP4K4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of 14C-glucose and 14C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of MAP4K4 fails to activate endogenous JNK, while MAP4K4 depletion does not attenuate JNK activation by tumor necrosis factor α. MAP4K4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with MAP4K4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show MAP4K4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that MAP4K4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that MAP4K4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.
Jason K Kim - One of the best experts on this subject based on the ideXlab platform.
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protein kinase mitogen activated protein kinase kinase kinase kinase 4 MAP4K4 promotes obesity induced hyperinsulinemia
2016Co-Authors: Rachel Roth J Flach, Laura V Danai, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Marina T Distefano, Mark J S Kelly, Agata Jurczyk, Rohit Sharma, Jason K KimAbstract:Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of MAP4K4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body MAP4K4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo. After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced β cell mass, fewer proliferating β cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase MAP4K4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from β cells in mice.
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inducible deletion of protein kinase MAP4K4 in obese mice improves insulin sensitivity in liver and adipose tissues
2015Co-Authors: Laura V Danai, Rachel Roth J Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K Kim, Michael P CzechAbstract:Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) attenuates insulin signaling, but confirmation in vivo is lacking since MAP4K4 knockout is lethal during embryogenesis. We thus generated mice with floxed MAP4K4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body MAP4K4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced MAP4K4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional MAP4K4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with MAP4K4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) MAP4K4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) MAP4K4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.