scholarly journals Activation of TFEB ameliorates dedifferentiation of arterial smooth muscle cells and neointima formation in mice with high-fat diet

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Yun-Ting Wang ◽  
Xiang Li ◽  
Jiajie Chen ◽  
Bradley K. McConnell ◽  
Li Chen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
High Fat Diet ◽  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Animal Experiments ◽  
Metabolic Stress ◽  
Neointima Formation ◽  
High Fat ◽  
Autophagy Pathway

Abstract Autophagy is recently implicated in regulating vascular smooth muscle cell (SMC) homeostasis and in the pathogenesis of vascular remodeling. Transcription factor EB (TFEB) is a master regulator of autophagy signaling pathways. However, the molecular mechanisms and functional roles of TFEB in SMC homeostasis have not been elucidated. Here, we surveyed the ability of TFEB to regulate autophagy pathway in SMCs, and whether pharmacological activation of TFEB favors SMC homeostasis preventing dedifferentiation and pathogenic vascular remodeling. In primary cultured SMCs, TFEB activator trehalose induced nuclear translocation of TFEB and upregulation of TFEB-controlled autophagy genes leading to enhanced autophagy signaling. Moreover, trehalose suppressed serum-induced SMC dedifferentiation to synthetic phenotypes as characterized by inhibited proliferation and migration. These effects of trehalose were mimicked by ectopic upregulation of TFEB and inhibited by TFEB gene silencing. In animal experiments, partial ligation of carotid arteries induced downregulation of TFEB pathway in the media layer of these arteries. Such TFEB suppression was correlated with increased SMC dedifferentiation and aggravated high-fat diet (HFD)-induced neointima formation. Treatment of mice with trehalose reversed this TFEB pathway suppression, and prevented SMC dedifferentiation and HFD-induced neointima formation. In conclusion, our findings have identified TFEB as a novel positive regulator for autophagy pathway and cellular homeostasis in SMCs. Our data suggest that suppression of TFEB may be an initiating mechanism that promotes SMC dedifferentiation leading to accelerated neointima formation in vascular disorders associated with metabolic stress, whereas trehalose reverses these changes. These findings warrant further evaluation of trehalose in the clinical settings.

scholarly journals Chronic High Fat Diet Intake Impairs Hepatic Metabolic Parameters in Ovariectomized Sirt3 KO Mice

2021 ◽  
Vol 22 (8) ◽  
pp. 4277
Author(s):  
Marija Pinterić ◽  
Iva I. Podgorski ◽  
Marijana Popović Hadžija ◽  
Ivana Tartaro Bujak ◽  
Ana Tadijan ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Metabolic Diseases ◽  
Body Weight Gain ◽  
Lipid Hydroperoxide ◽  
Metabolic Stress ◽  
Lipid Hydroperoxides ◽  
Ros Scavenging ◽  
High Fat ◽  
Preclinical Research ◽  
Female Mice

High fat diet (HFD) is an important factor in the development of metabolic diseases, with liver as metabolic center being highly exposed to its influence. However, the effect of HFD-induced metabolic stress with respect to ovary hormone depletion and sirtuin 3 (Sirt3) is not clear. Here we investigated the effect of Sirt3 in liver of ovariectomized and sham female mice upon 10 weeks of feeding with standard-fat diet (SFD) or HFD. Liver was examined by Folch, gas chromatography and lipid hydroperoxide analysis, histology and oil red staining, RT-PCR, Western blot, antioxidative enzyme and oxygen consumption analyses. In SFD-fed WT mice, ovariectomy increased Sirt3 and fatty acids synthesis, maintained mitochondrial function, and decreased levels of lipid hydroperoxides. Combination of ovariectomy and Sirt3 depletion reduced pparα, Scd-1 ratio, MUFA proportions, CII-driven respiration, and increased lipid damage. HFD compromised CII-driven respiration and activated peroxisomal ROS scavenging enzyme catalase in sham mice, whereas in combination with ovariectomy and Sirt3 depletion, increased body weight gain, expression of NAFLD- and oxidative stress-inducing genes, and impaired response of antioxidative system. Overall, this study provides evidence that protection against harmful effects of HFD in female mice is attributed to the combined effect of female sex hormones and Sirt3, thus contributing to preclinical research on possible sex-related therapeutic agents for metabolic syndrome and associated diseases.

scholarly journals Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus

2017 ◽  
Vol 59 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Long The Nguyen ◽  
Sonia Saad ◽  
Yi Tan ◽  
Carol Pollock ◽  
Hui Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Mrna Level ◽  
Metabolic Stress ◽  
High Fat ◽  
Chemical Chaperone ◽  
Protein Levels

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

scholarly journals Baicalin Attenuates High Fat Diet-Induced Obesity and Liver Dysfunction: Dose-Response and Potential Role of CaMKKβ/AMPK/ACC Pathway

2015 ◽  
Vol 35 (6) ◽  
pp. 2349-2359 ◽  
Author(s):  
Youli Xi ◽  
Miaozong Wu ◽  
Hongxia Li ◽  
Siqi Dong ◽  
Erfei Luo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Serum Levels ◽  
Whole Body ◽  
Therapeutic Effects ◽  
High Fat ◽  
Dependent Protein

Background/Aims: Obesity-associated fatty liver disease affects millions of individuals. This study aimed to evaluate the therapeutic effects of baicalin to treat obesity and fatty liver in high fat diet-induced obese mice, and to study the potential molecular mechanisms. Methods: High fat diet-induced obese animals were treated with different doses of baicalin (100, 200 and 400 mg/kg/d). Whole body, fat pad and liver were weighed. Hyperlipidemia, liver steatosis, liver function, and hepatic Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ) / AMP-activated protein kinase (AMPK) / acetyl-CoA carboxylase (ACC) were further evaluated. Results: Baicalin significantly decreased liver, epididymal fat and body weights in high fat diet-fed mice, which were associated with decreased serum levels of triglycerides, total cholesterol, LDL, alanine transaminase and aspartate transaminase, but increased serum HDL level. Pathological analysis revealed baicalin dose-dependently decreased the degree of hepatic steatosis, with predominantly diminished macrovesicular steatosis at lower dose but both macrovesicular and microvesicular steatoses at higher dose of baicalin. Baicalin dose-dependently inhibited hepatic CaMKKβ/AMPK/ACC pathway. Conclusion: These data suggest that baicalin up to 400 mg/kg/d is safe and able to decrease the degree of obesity and fatty liver diseases. Hepatic CaMKKβ/AMPK/ACC pathway may mediate the therapeutic effects of baicalin in high fat diet animal model.

scholarly journals Maintenance of AMPK activation by metformin is beneficial for suppressing the progress of diabetes-accelerated atherosclerosis via inhibition of vascular smooth muscle cells migration

2020 ◽  
Author(s):  
Yi Yan ◽  
Ting Li ◽  
Zhonghao Li ◽  
Mingyuan He ◽  
Dejiang Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Fat Diet ◽  
Muscle Cells ◽  
Atherosclerotic Plaques ◽  
Ampk Activation ◽  
High Fat ◽  
Accelerated Atherosclerosis

Abstract Background: Our previous work revealed that augmented AMPK activation inhibit cell migration by phosphorylating its substrate Pdlim5. As medial VSMCs contribute to the major composition of atherosclerotic plaques, a hypothesis is raised that modulation of AMPK-Pdlim5 signal pathway could retard the development of atherosclerosis through inhibiting migration of VSMCs. Therefore, we initiate the present study to investigate whether AMPK agonist like metformin is beneficial for suppressing diabetes-accelerated atherosclerosis in a diabetic mouse model induced by streptozotocin and high fat diet.Methods: For cell experiment, vascular smooth muscle cells (VSMCs) were overexpressed flag fused Pdlim5 and Pdlim5 mutant. Then the engineered VSMCs were introduced with metformin or control drug before determination of phosphorylated Pdlim5 with immunoblotting. For animal work, 8-week-old male ApoE−/−mice were induced diabetes with streptozotocin and then were randomly divided into 8 groups: control group, metformin hydrochloride (300 mg/kg/day) group, wildtype-Pdlim5 (Pdlim5 WT) carried adenovirus (Ad) group, Ad Pdlim5 WT and Met group, Ad Pdlim5 S177A group, Ad Pdlim5 S177A and Met group, Ad Pdlim5 S177D group, Ad Pdlim5 S177D and Met group. All mice were fed with high fat diet after virus infection. At the end, mice were sacrificed to observe atherosclerotic plaques and deposition of VSMCs in plaques. Moreover, 12–15-week-old Myh11-cre-EGFP male mice were accepted ligation of the left carotid artery and randomly divided into control and metformin treatment group. Finally, the injured vessel of Myh11-cre-EGFP mice were isolated to analyze the relationship between AMPK activation and neointima formation.Results: It was found that AMPK directly phosphorylate Pdlim5 at Ser177 in vitro, and metformin, an AMPK agonist, could induce phosphorylation of Pdlim5 indirectly and inhibition of cell migration as a result. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits lamellipodia formation and migration in VSMCs. It was also demonstrated that VSMCs contribute to the major composition of injury-induced neointimal lesions, while metformin could alleviate the occlusion of carotid artery in a wire-injury mice model. In order to investigate the function of AMPK-Pdlim5 pathway in the context of pathological condition, ApoE−/− male mice were divided randomly into control, streptozocin and high fat diet-induced diabetes mellitus, STZ + HFD together with metformin or Pdlim5 mutant carried adenovirus treatment groups. The results showed increased plasma lipids and aggravated vascular smooth muscle cells infiltration into the atherosclerotic lesion in diabetic mice compared with control mice. However, metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as decreased VSMCs infiltration in atherosclerotic plaques, while Pdlim5 phospho-abolished mutant carried adenovirus S177A-Pdlim5 undermine this protective function.Conclusions: The activation of AMPK-Pdlim5 pathway by chemicals like Metformin could inhibit formation of migratory machine of VSMCs and alleviate the progress of atherosclerotic plaques in diabetic mice. The maintenance of AMPK activity is beneficial for suppressing diabetes-accelerated atherosclerosis or metabolic syndrome.

Abstract 16456: Regulation of Vascular Smooth Muscle Phenotypic Switch and Suppression of Atherosclerosis by c-Kit/SCF Expression in Hyperlipidemic Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Lei Song ◽  
Annia Mesa ◽  
Natasha Fernandez ◽  
Guillermo Selman ◽  
Nieves Santos ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
High Fat Diet ◽  
Phenotypic Switching ◽  
High Fat ◽  
Phenotypic Switch ◽  
Tnf Α ◽  
Mutant Strains ◽  
Synthetic Phenotype ◽  
Pro Inflammatory Cytokines

Introduction: This study provides our novel evidence that stem cell factor (SCF) receptor c-Kit regulates vascular smooth muscle cell (SMC) phenotype and is potently anti-atherogenic. Methods and Results: Atherosclerotic plaque was quantified in transgenic mice deficient for c-Kit (c-Kit W/Wv ApoE -/- ) or SCF (c-Kitl sl /+ ApoE -/- ) after 16 weeks of high fat diet (HFD). Both mutant strains displayed substantially greater atherosclerosis compared with control (ApoE -/- ) littermates ( p <0.01 and <0.05 respectively). Transplantation of c-Kit positive bone marrow into c-Kit W/Wv ApoE -/- mice failed to rescue the atherogenic phenotype indicating that increased atherosclerosis was associated with reduced arterial c-Kit. To investigate the mechanism, SMC organization and morphology were analyzed in aorta by histopathology and electron microscopy. Remarkably, SMCs were more abundant, disorganized and vacuolated in aortas of c-Kit mutant mice compared with controls ( p <0.05). Markers of the “contractile” SMC phenotype (Calponin, SM22α) were downregulated in parallel with decreased c-Kit ( p <0.05). Reconstitution of c-Kit in synthetic cultured SMCs conferred increased spindle-shaped morphology, reduced proliferation and elevated levels of contractile markers Calponin and SM22α, each characteristic of a resumed contractile phenotype ( p <0.05). Conversely, aortas of c-Kit W/Wv ApoE -/- accumulated more pro-inflammatory cytokines (MCP-1, RANTES, MIP-1β, G-CSF, p <0.01) and elevated monocytes compared with control mice treated equivalently. Additionally, quantitative mRNA screening and western blot analysis revealed elevated levels of atherosclerotic and inflammatory biomarkers Toll Like Receptors (TLR4, 6, 9) and TNF-α in cultures of c-Kit W/Wv VS c-Kit +/+ SMC. Conclusion: c-Kit/SCF expression prevents phenotypic switching of contractile SMC to the pro-inflammatory, synthetic phenotype and markedly suppresses atherosclerosis in this murine model.

Abstract P430: VSMCs Increase Glutamine Utilization For Energy Metabolism During Obesity

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Krystal M Roggerson ◽  
Sharon Francis
Keyword(s):  
Oxygen Consumption ◽  
Energy Metabolism ◽  
High Fat Diet ◽  
Vascular Remodeling ◽  
Energy Demand ◽  
Critical Role ◽  
Fold Increase ◽  
Metabolic Reprogramming ◽  
High Fat ◽  
Low Fat

Obesity increases the risk of developing cardiovascular disease through vascular remodeling though the underlying mechanisms are not entirely understood. However, metabolic fuel partitioning and mitochondrial flexibility during energy metabolism may play a critical role. We demonstrated serum and glucocorticoid-inducible kinase 1 (SGK-1) is up-regulated in the vasculature of diet-induced obese mice and that SGK-1 deletion is protective against obesity-induced vascular remodeling by metabolically reprogramming vascular smooth muscle cell (VSMC) energy metabolism towards oxidative phosphorylation (OXPHOS) and away from glycolysis. Mitochondrial substrate availability and utilization of the primary metabolic fuels glucose, long chain fatty acids (LCFAs) and glutamine can drive metabolic reprogramming. Therefore, alterations in fuel utilization may contribute to vascular remodeling during obesity. The purpose of this study was to examine SGK-1’s role in 1) fuel dependency: a cell’s reliance for a specific fuel and 2) fuel capacity: a cell’s ability to oxidize a specific fuel to meet cellular energy demand under low-fat and high-fat diet-induced obesity. Using the MitoXpress Oxygen Consumption assay which measures OXPHOS, primary VSMCs isolated from wildtype (WT) and SMC-specific SGK-1 knockout (smSGK-1 KO) mice fed a 10% kcal low-fat or 45% kcal high-fat diet for eight weeks were seeded in a 96-well plate at a density of 6x10 4 cells/well in culture medium. To assess fuel dependency, cells were treated with fuel pathway inhibitors UK5099, Etomoxir or BPTES to block glucose, LCFA or glutamine oxidation, respectively. To measure fuel capacity, VSMCs were treated with a combination of two pathway inhibitors simultaneously. Next, samples were overlaid with a fluorescent extracellular oxygen consumption reagent, sealed with high-sensitivity mineral oil, then signals were read at 1.5-minute intervals for 2 hours at Ex/Em= 380/650 nm. Our results show WT VSMCs are exclusively glucose-dependent for OXPHOS regardless of dietary conditions. However, SGK-1 deletion induces a dependency for all three fuels for OXPHOS in VSMCs under low- and high-fat conditions. Even though WT and smSGK-1 KO VSMCs preferentially oxidized glucose for OXPHOS under low-fat conditions; SGK-1 deletion resulted in a 2.2-fold increase in glutamine capacity. Alternatively, WT VSMCs exposed to obesogenic conditions preferentially oxidized glutamine whereas SGK-1 deletion induced a nearly equal partitioning of all three fuels during obesity suggesting elevated mitochondrial flexibility. Overall, this study suggests SGK-1 increases glucose dependency for energy metabolism under physiological and obesogenic conditions. Also, increased glutamine utilization for OXPHOS during obesity may be an underlying cause of VSMC dysfunction and subsequent vascular impairment.

Abstract 353: Chronic Polarization of Low-grade Inflammatory Monocytes During the Pathogenesis of Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Liwu Li ◽  
Shuo Geng
Keyword(s):  
High Fat Diet ◽  
Immunohistochemical Staining ◽  
Molecular Mechanisms ◽  
Molecular Switches ◽  
Low Grade ◽  
High Fat ◽  
Inflammatory Monocytes ◽  
Severe Atherosclerosis ◽  
Low Grade Inflammation ◽  
Deficient Mice

Background: Chronic inflammation mediated by low-grade inflammatory monocytes may serve as a key culprit for atherosclerosis. However, the cellular and molecular mechanisms responsible for the low-grade inflammatory polarization of monocytes are not well understood. We hypothesize that the selective clearance of homeostatic molecular switches may pre-dispose innate monocytes for the establishment of non-resolving low-grade inflammation. Methods and Results: By comparing high-fat-diet (HFD) fed ApoE deficient mice chronically challenged with either PBS or a subclinical dose endotoxin, we observed that subclinical endotoxin potently induced the establishment of low-grade inflammation, as manifested in elevated levels of systemic inflammatory mediators, accumulation of low-grade inflammatory circulating monocytes and neutrophils, as well as lipids. Immunohistochemical staining of liver and aorta tissues revealed significantly elevated steatosis and atherosclerosis in ApoE deficient mice chronically challenged with subclinical dose of endotoxin. At the mechanistic level, the polarization of low-grade inflammatory monocytes were due to the down-regulation and removal of key homeostatic molecules such as IRAK-M and Tollip. ApoE and IRAK-M double deficient mice had enhanced inflammatory polarization of innate monocytes, and developed severe atherosclerosis. Conclusions: Our data suggest that the clearance of homeostatic suppressors such as IRAK-M and Tollip may cause the memory establishment of low-grade inflammatory monocytes that are conducive for the chronic pathogenesis of atherosclerosis. Key words: Low-grade inflammation, monocyte polarization, innate memory, atherosclerosis

Abstract 498: The Effects of Low-carbohydrate High-fat Diet on Vascular Remodeling

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Haruka Yanagisawa ◽  
Haruhiro Toko ◽  
Mutsuo Harada ◽  
Jiaxi Guo ◽  
Satoshi Bujo ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Vascular Remodeling ◽  
High Fat ◽  
Low Carbohydrate

scholarly journals Yarrow Supercritical Extract Ameliorates the Metabolic Stress in a Model of Obesity Induced by High-Fat Diet

Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 72 ◽  
Author(s):  
Lamia Mouhid ◽  
Marta Gómez de Cedrón ◽  
Adriana Quijada-Freire ◽  
Pablo J. Fernández-Marcos ◽  
Guillermo Reglero ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Metabolic Stress ◽  
Standard Diet ◽  
Model Assessment ◽  
High Fat ◽  
Glucose Levels ◽  
Nutraceutical Compounds ◽  
Fasting Glycemia ◽  
Obesity And Diabetes ◽  
Potential Therapeutic Role

Nowadays, obesity and its associated metabolic disorders, including diabetes, metabolic syndrome, cardiovascular disease, or cancer, continue to be a health epidemic in westernized societies, and there is an increased necessity to explore anti-obesity therapies including pharmaceutical and nutraceutical compounds. Considerable attention has been placed on the identification of bioactive compounds from natural sources to manage the metabolic stress associated with obesity. In a previous work, we have demonstrated that a CO2 supercritical fluid extract from yarrow (Yarrow SFE), downregulates the expression of the lipogenic master regulator SREBF1 and its downstream molecular targets FASN and SCD in a tumoral context. Since obesity and diabetes are strongly considered high-risk factors for cancer development, herein, we aimed to investigate the potential therapeutic role of Yarrow SFE in the metabolic stress induced after a high-fat diet in mice. For this purpose, 32 C57BL/6 mice were distributed in four groups according to their diets: standard diet (SD); SD supplemented with Yarrow SFE (SD + Yarrow); high-fat diet (HFD); and HFD supplemented with Yarrow SFE (HFD + Yarrow). Fasting glycemia, insulin levels, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile, gene expression, and lipid content of liver and adipose tissues were analyzed after three months of treatment. Results indicate improved fasting glucose levels in plasma, enhanced insulin sensitivity, and diminished hypercholesterolemia in the HFD + Yarrow group compared to the HFD group. Mechanistically, Yarrow SFE protects liver from steatosis after the HFD challenge by augmenting the adipose tissue buffering capacity of the circulating plasma glucose.

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