The TBK1/IKKe Inhibitor Amlexanox Improves Dyslipidemia and Prevents Atherosclerosis
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PROVIDER: PRJNA861838 | ENA |
REPOSITORIES: ENA
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Project description:Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the non-canonical IkB kinases TBK1 and IKKe with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human subjects. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet (WD)-fed Ldlr-/- mice, and protects against atherogenesis. Amlexanox ameliorates dyslipidemia, inflammation and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrates an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuates monocytosis, eosinophilia and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a new therapy for hypercholesterolemia and atherosclerosis.
2022-07-27 | GSE209621 | GEO
Project description:Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet-fed (WD-fed) Ldlr-/- mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.
| S-EPMC9536260 | biostudies-literature
Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/ IKKe. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes TBK1/IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, SON, TBK1, IKKe, IKKb, and NFkB p65. The purified hnRNPM complex enhanced TBK1 phosphorylation. Vice versa, TBK1 directly phosphorylated ELAVL1. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol close to the nuclear membrane. Of note, patients with mutations in SON suffer from recurrent infections, underlining its biologic significance. To our knowledge, hnRNPM, ELAVL1, and SON represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.
2024-11-11 | PXD028160 | Pride
Project description:Abstract Cardiovascular disease (CVD) is closely associated with obesity through risk factors such as dyslipidemia and chronic low-grade inflammation, which may be affected by diet. Dietary fats have been extensively studied in relation to CVD risk, however these studies have not always yielded consistent results, most likely due to lack in control of experimental conditions and confounding factors. Here we studied the effects of different plant and animal fats on dyslipidemia, inflammation and atherosclerosis. Ldlr-/-.Leiden mice were fed isocaloric energy-dense diets with translational macronutrient composition for 28 weeks. The diets were identical apart from the type of fat they contained: either 1) a mixture of olive and rapeseed oil; 2) sunflower oil; 3) pork fat; 4) beef fat; or 5) milk fat. The fatty acid composition of the diets was determined and effects on circulating lipid and inflammatory risk factors and atherosclerosis were examined, complemented by adipose tissue histology and liver transcriptomics. While visceral fat mass, adipocyte size and adipose tissue inflammation were not differentially affected by the diets, atherosclerotic lesion load and severity was more pronounced with increasing dietary saturated fatty acid content and decreasing monounsaturated and polyunsaturated fatty acid content, and hence most pronounced with beef and milk fat. These differential effects were accompanied by increases in pro-atherogenic plasma lipids/lipoproteins (e.g., triglycerides, apolipoprotein B), activation of pro-atherogenic cytokine/chemokine signaling pathways in liver, and with circulating pro-atherogenic mediators of inflammation altogether providing a rationale for the differential effects of plant and animal fats.
2023-12-21 | GSE232133 | GEO
Project description:Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. It has been postulated that accumulation of visceral adipose tissue (VAT) causes obesity-induced insulin resistance. The major purpose of this study was to test hypothesis that prophylactic VAT removal prevents the development of obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance, dyslipidemia, and NAFLD. Accordingly, we surgically removed epididymal VAT from adult C57BL/6J mice and then evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following feeding of chronic high-fat diet (HFD). We found that VAT removal prevented HFD-induced insulin resistance and markedly increased AKT-mediated insulin signaling in subcutaneous adipose tissue (SAT), liver, and skeletal muscle. VAT removal improved plasma lipid profiling and prevented obesity-induced NAFLD. In addition, VAT removal significantly increased circulating level of adiponectin, a key insulin-sensitizing adipokine, whereas it decreased interleukin-6, a pro-inflammatory adipokine. Data obtained from RNA-sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT respectively. These findings demonstrate the causative role of VAT in the development of obesity and related systemic metabolic complications, such as insulin resistance, dyslipidemia, and NAFLD.
2021-04-01 | GSE157798 | GEO
Project description:Differential effects of plant- and animal fats on obesity-induced dyslipidemia and atherosclerosis
| PRJNA971103 | ENA
Project description:Dyslipidemia and inflammation play key roles in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. NAFLD, particularly its severe form nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease (CVD) risk. HDL (high density lipoprotein- also a CVD risk) are decreased in NAFLD but whether HDL function is abnormal in NAFLD is unknown. Furthermore, it is unknown whether dyslipidemia contributes to reduced HDL function in NAFLD and whether hepatic inflammation further impairs HDL function in patients with NASH. Therefore, the aim of this study was to investigate HDL function and to examine the effect of dyslipidemia and inflammation on HDL metabolism in patients with biopsy-proven simple steatosis (SS) and NASH. RESULTS: Compared to controls, SS and NASH subjects had significantly higher levels of plasma triglyceride, insulin, and were more insulin resistant (HOMA, P<0.05) with no differences in total cholesterol, HDL cholesterol, ApoB100 and ApoAI levels. NAFLD patients had increased production and degradation rates of both HDLc and ApoAI that resulted in their levels remaining stable. The degradation rates also were increased of other HDL proteins, including ApoAII, ApoAIV, vitamin D-binding protein, and complement 3 (all P<0.05). NAFLD patients had increased activities of LCAT and CETP, indicating altered HDL lipidation. NAFLD induced alterations in HDL metabolism were associated with reduced anti-oxidant but increased pro-inflammatory activity of HDL. However, no differences were observed in either HDL function or the kinetics of HDLc and HDL proteins between SS and NASH subjects.
2019-08-12 | PXD010199 | Pride
Project description:B-DNA-induced gene expression profile in wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats; to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses. Experiment Overall Design: Total RNA was extracted from embryonic fibroblats transfected for 4 h with or without poly(dA-dT)-poly(dT-dA), after which cRNA was synthesized. Preparation of cRNA, hybridization and scanning of the microarray were done according to the manufacturer's instructions (Affymetrix). A microarray (MG U74A version 2; Affymetrix) was used with Microarray Suite software (version 5.0; Affymetrix) and GeneSpring software (Silicon Genetics).
2007-12-07 | E-GEOD-4171 | biostudies-arrayexpress
Project description:Ubiquitination of hepatic APOC3 by GM47544 prevents hypertriglyceridemia and ameliorates atherosclerosis
| PRJNA974253 | ENA
Project description:Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP-deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggest IRE1 inhibition as a promising new way to counteract atherosclerosis.
2022-02-15 | PXD030594 | Pride