Cachexia-inducible Transforming growth factor-beta1 stimulated Clone-22 D4 controls acute hepatic lipid homeostasis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE33324 | GEO | 2012/09/01
SECONDARY ACCESSION(S): PRJNA148987
REPOSITORIES: GEO
Similar Datasets
Project description:To explore the molecular basis for TSC22D4 function in hepatic lipid homeostasis in vivo TSC22D4 was knocked down in the mouse liver using adenovirus and performed genome wide expression analysis. 1x10^9 plaque-forming units (pfu) per recombinant virus were administered via tail vein injection. Mice (C57Bl/6) were sacrificed 7 days after infection. Hepatic RNA was isolated and used for whole genome expression analysis.
2012-09-01 | E-GEOD-33324 | biostudies-arrayexpress
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy. 28 BKS.Cg-Dock7m +/+ Leprdb/J (000642) mice (12 week old ) were divided to 4 forms of treatment (n=7 per treatment group) consisting of 4 different shRNA adenoviruses (reference sample: control shRNA), LCN13 (LCN13 shRNA), TSC22D4 (TSC22D4 shRNA), TSC22D4 plus LCN13 (TSC22D4+LCN13 shRNA). 1 week after shRNA injection animals were sacrificed, liver, abdominal fat tissue, gastrocnemius tissue was immediately snap frozen. 3 representative animals of each treatment group were selected for microarray analysis (abdominal fat tissue).
2014-10-15 | E-GEOD-53753 | biostudies-arrayexpress
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis –in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.
2014-10-15 | GSE53754 | GEO
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.
2014-10-15 | GSE53753 | GEO
Project description:Disturbances in lipid homeostasis are hallmarks of severe metabolic disorders and their long-term complications, including obesity, diabetes, and atherosclerosis. Whereas elevation of triglyceride (TG)-rich very-low-density lipoproteins (VLDL) has been identified as a risk factor for cardiovascular complications, high-density lipoprotein (HDL)-associated cholesterol confers atheroprotection under obese and/or diabetic conditions. Here we show that hepatocyte-specific deficiency of transcription factor transforming growth factor ? 1-stimulated clone (TSC) 22 D1 led to a substantial reduction in HDL levels in both wild-type and obese mice, mediated through the transcriptional down-regulation of the HDL formation pathway in liver. Indeed, overexpression of TSC22D1 promoted high levels of HDL cholesterol in healthy animals, and hepatic expression of TSC22D1 was found to be aberrantly regulated in disease models of opposing energy availability. The hepatic TSC22D1 transcription factor complex may thus represent an attractive target in HDL raising strategies in obesity/diabetes-related dyslipidemia and atheroprotection.
| S-EPMC3953693 | biostudies-literature
Project description:c-MYC stimulates cell proliferation through the suppression of cyclin-dependent kinase (CDK) inhibitors including P15 (CDKN2B) and P21 (CDKN1A). It also activates E-box-mediated transcription of various target genes including telomerase reverse transcriptase (TERT) that is involved in cellular immortality and tumorigenesis. Transforming growth factor-beta 1 (TGF-?1)-stimulated clone 22 (TSC-22/TSC22D1) encodes a highly conserved leucine zipper protein that is induced by various stimuli, including TGF-?. TSC-22 inhibits cell growth in mammalian cells and in Xenopus embryos. However, underlying mechanisms of growth inhibition by TSC-22 remain unclear. Here, we show that TSC-22 physically interacts with c-MYC to inhibit the recruitment of c-MYC on the P15 (CDKN2B) and P21 (CDKN1A) promoters, effectively inhibiting c-MYC-mediated suppression of P15 (CDKN2B) and also P21 (CDKN1A) promoter activities. In contrast, TSC-22 enhances c-MYC-mediated activation of the TERT promoter. Additionally, the expression of TSC-22 in embryonic stem cells inhibits cell growth without affecting its pluripotency-related gene expression. These results indicate that TSC-22 differentially regulates c-MYC-mediated transcriptional activity to regulate cell proliferation.
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Project description:Transforming growth factor-beta1 (TGF-beta1) is the most abundant TGF-beta isoform detected in bone and is an important functional modulator of osteoclasts. TGF-beta1 can induce osteoclast apoptosis; however, the apoptotic pathways involved in this process are not known. We show here that human osteoclasts express both type-I and type-II TGF-beta receptors. In the absence of survival factors, TGF-beta1 (1 ng/ml) induced osteoclast apoptosis. The expression of activated caspase-9, but not that of caspase-8, was increased by TGF-beta1 stimulation, and the rate of TGF-beta1-induced apoptosis was significantly lower in the presence of a caspase-9 inhibitor. To study further the mechanisms involved in TGF-beta1-induced osteoclast apoptosis, we investigated TGF-beta1 signaling, which primarily involves the Smad pathway, but also other pathways that may interfere with intracellular modulators of apoptosis, such as mitogen-activated protein (MAP) kinases and Bcl2 family members. We show here that early events consisted of a trend toward increased expression of extracellular signal-regulated kinase (ERK), and then TGF-beta1 significantly induced the activation of p38 and Smad2 in a time-dependent manner. These signaling cascades may activate the intrinsic apoptosis pathway, which involves Bim, the expression of which was increased in the presence of TGF-beta1. Furthermore, the rate of TGF-beta1-induced osteoclast apoptosis was lower when Bim expression was suppressed, and inhibiting the Smad pathway abolished Bim up-regulation following TGF-beta stimulation. This could correspond to a regulatory mechanism involved in the inhibition of osteoclast activity by TGF-beta1.
| S-EPMC2749113 | biostudies-literature
Project description:BackgroundUnderstanding the underlying mechanisms of neuropathic pain caused by damage to the peripheral nervous system remains challenging and could lead to significantly improved therapies. Disturbance of homeostasis not only occurs at the site of injury but also extends to the spinal cord and brain involving various types of cells. Emerging data implicate neuroimmune interaction in the initiation and maintenance of chronic pain hypersensitivity.ResultsIn this study, we sought to investigate the effects of TGF-beta1, a potent anti-inflammatory cytokine, in alleviating nerve injury-induced neuropathic pain in rats. By using a well established neuropathic pain animal model (partial ligation of the sciatic nerve), we demonstrated that intrathecal infusion of recombinant TGF-beta1 significantly attenuated nerve injury-induced neuropathic pain. TGF-beta1 treatment not only prevents development of neuropathic pain following nerve injury, but also reverses previously established neuropathic pain conditions. The biological outcomes of TGF-beta1 in this context are attributed to its pleiotropic effects. It inhibits peripheral nerve injury-induced spinal microgliosis, spinal microglial and astrocytic activation, and exhibits a powerful neuroprotective effect by preventing the induction of ATF3+ neurons following nerve ligation, consequently reducing the expression of chemokine MCP-1 in damaged neurons. TGF-beta1 treatment also suppresses nerve injury-induced inflammatory response in the spinal cord, as revealed by a reduction in cytokine expression.ConclusionOur findings revealed that TGF-beta1 is effective in the treatment of neuropathic by targeting both neurons and glial cells. We suggest that therapeutic agents such as TGF-beta1 having multipotent effects on different types of cells could work in synergy to regain homeostasis in local spinal cord microenvironments, therefore contributing to attenuate neuropathic pain.
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Project description:Fibrosis is a pathological process characterized by infiltration and proliferation of mesenchymal cells in interstitial space. A substantial portion of these cells is derived from residing non-epithelial and/or epithelial cells that have acquired the ability to migrate and proliferate. The mesenchymal transition is also observed in cancer cells to confer the ability to metastasize. Here, we show that renal fibrosis induced by unilateral ureteral obstruction and metastasis of human cancer xenografts are suppressed by administration of secreted Klotho protein to mice. Klotho is a single-pass transmembrane protein expressed in renal tubular epithelial cells. The extracellular domain of Klotho is secreted by ectodomain shedding. Secreted Klotho protein directly binds to the type-II TGF-? receptor and inhibits TGF-?1 binding to cell surface receptors, thereby inhibiting TGF-?1 signaling. Klotho suppresses TGF-?1-induced epithelial-to-mesenchymal transition (EMT) responses in cultured cells, including decreased epithelial marker expression, increased mesenchymal marker expression, and/or increased cell migration. In addition to TGF-?1 signaling, secreted Klotho has been shown to inhibit Wnt and IGF-1 signaling that can promote EMT. These results have raised the possibility that secreted Klotho may function as an endogenous anti-EMT factor by inhibiting multiple growth factor signaling pathways simultaneously.
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Project description:Transforming growth factor beta1 (TGFbeta1) expression is elevated by tumor promoters in the mouse skin, but its role in tumor promotion has not been well defined. To investigate this, we have compared TGFbeta1+/+ and +/- mice in a two-stage skin chemical carcinogenesis protocol. Surprisingly, TGFbeta1+/- mice had fewer number and incidence of benign papillomas, reduced epidermal and tumor cell proliferation and reduced epidermal TGFbeta1 and nuclear p-Smad2 localization in response to the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) compared with TGFbeta1+/+ mice. Maximal TPA activation of protein kinase C (PKCalpha) as measured by activity assays and activation of target genes and induction of cornified envelopes correlated with TGFbeta1 gene dosage in keratinocytes and addition of exogenous TGFbeta1 restored the cornification defect in TGFbeta1+/- keratinocytes. Similarly, inhibition of ALK5-suppressed TPA-mediated PKCalpha activation suggesting that physiological levels of TGFbeta1 are required for maximal activation of PKC-dependent mitogenic responses. Paradoxically, the TPA-induced inflammatory response was greater in TGFbeta1+/- skin, but TGFbeta1+/+ papillomas had more tumor infiltrating myeloperoxidase-positive cells and pro-inflammatory gene expression was elevated in v-ras(Ha)-transduced TGFbeta1+/+ but not TGFbeta1+/- keratinocytes. Thus, ras activation switches TGFbeta1 to a pro-inflammatory cytokine. Despite this differential proliferative and inflammatory response to TPA and enhanced papilloma formation in the TGFbeta1+/+ mice, the frequency of malignant conversion was reduced compared with TGFbeta1+/- mice. Therefore, TGFbeta1 promotes benign tumors by modifying tumor promoter-induced cell proliferation and inflammation but retains a suppressive function for malignant conversion.
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