scholarly journals Palmitoylated small GTPase ARL15 is translocated within Golgi network during adipogenesis

Biology Open ◽  
2021 ◽  
Author(s):  
Yixing Wu ◽  
Ying Bai ◽  
David G. McEwan ◽  
Liz Bentley ◽  
Dimitra Aravani ◽  
...  
Keyword(s):  
Cell Line ◽  
Small Gtpase ◽  
Loss Of Function ◽  
White Adipocyte ◽  
Increased Risk ◽  
Mild Reduction ◽  
Adipocyte Cell ◽  
Golgi Network

The small GTPase ARF family member ARL15 gene locus is associated in population studies with increased risk of type 2 diabetes, lower adiponectin and higher fasting insulin levels. Previously, loss of ARL15 was shown to reduce insulin secretion in a human β-cell line and loss of function mutations are found in some lipodystrophy patients. We set out to understand the role of ARL15 in adipogenesis and showed that endogenous ARL15 palmitoylated and localised in the Golgi of mouse liver. Adipocyte overexpression of palmitoylation-deficient ARL15 resulted in redistribution to the cytoplasm and a mild reduction in expression of some adipogenesis-related genes. Further investigation of the localisation of ARL15 during differentiation of a human white adipocyte cell line showed that ARL15 was predominantly co-localised with a marker of the cis face of Golgi at the preadipocyte stage and then translocated to other Golgi compartments after differentiation was induced. Finally, co-immunoprecipitation and mass spectrometry identified potential interacting partners of ARL15, including the ER-localised protein ARL6IP5. Together, these results suggest a palmitoylation dependent trafficking-related role of ARL15 as a regulator of adipocyte differentiation via ARL6IP5 interaction.

The GSTM1 and GSTT1 Null Genotypes Increase the Risk for Type 2 Diabetes Mellitus and the Subsequent Development of Diabetic Complications: A Meta-analysis

2018 ◽  
Vol 15 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Sayantan Nath ◽  
Sambuddha Das ◽  
Aditi Bhowmik ◽  
Sankar Kumar Ghosh ◽  
Yashmin Choudhury
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Meta Analysis ◽  
Subsequent Development ◽  
Asian Population ◽  
Gstm1 Null Genotype ◽  
Increased Risk

Background:Studies pertaining to association of GSTM1 and GSTT1 null genotypes with risk of T2DM and its complications were often inconclusive, thus spurring the present study.Methods:Meta-analysis of 25 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in determining the risk for T2DM and 17 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in development of T2DM related complications were conducted.Results:Our study revealed an association between GSTM1 and GSTT1 null polymorphism with T2DM (GSTM1; OR=1.37;95% CI =1.10-1.70 and GSTT1; OR=1.29;95% CI =1.04-1.61) with an amplified risk of 2.02 fold for combined GSTM1-GSTT1 null genotypes. Furthermore, the GSTT1 null (OR=1.56;95%CI=1.38-1.77) and combined GSTM1-GSTT1 null genotypes (OR=1.91;95%CI=1.25- 2.94) increased the risk for development of T2DM related complications, but not the GSTM1 null genotype. Stratified analyses based on ethnicity revealed GSTM1 and GSTT1 null genotypes increase the risk for T2DM in both Caucasians and Asians, with Asians showing much higher risk of T2DM complications than Caucasians for the same. </P><P> Discussion: GSTM1, GSTT1 and combined GSTM1-GSTT1 null polymorphism may be associated with increased risk for T2DM; while GSTT1 and combined GSTM1-GSTT1 null polymorphism may increase the risk of subsequent development of T2DM complications with Asian population carrying an amplified risk for the polymorphism.Conclusion:Thus GSTM1 and GSTT1 null genotypes increases the risk for Type 2 diabetes mellitus alone, in combination or with regards to ethnicity.

scholarly journals Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Hugo Christian Monroy-Ramírez ◽  
Marina Galicia-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
White Adipocyte ◽  
Peroxisome Proliferator Activated Receptors ◽  
And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

scholarly journals CIC missense variants contribute to susceptibility for spina bifida

2021 ◽  
Author(s):  
Xiao Han ◽  
Xuanye Cao ◽  
Vanessa Aguiar-Pulido ◽  
Wei Yang ◽  
Menuka Karki ◽  
...  
Keyword(s):  
Spina Bifida ◽  
Cell Line ◽  
Neural Tube ◽  
Folate Receptor ◽  
Spinocerebellar Ataxia Type ◽  
Loss Of Function ◽  
Missense Variants ◽  
Increased Risk ◽  
Cell Line Hela

Neural Tube Defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to cerebral folate deficiency by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased risk for NTDs by depressing embryonic folate concentrations. In this study, we examined CIC variants from whole genome sequencing (WGS) data of 140 isolated spina bifida cases and identified 8 missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased FOLR1 protein level and planar cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a murine cell line (NIH3T3), CIC loss of function variants down regulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD.

Role of Circulating Microparticles in Type 2 Diabetes Mellitus: Implications for Pathological Clotting

2021 ◽  
Author(s):  
Siphosethu Cassandra Maphumulo ◽  
Etheresia Pretorius
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Systemic Inflammation ◽  
Blood Cells ◽  
Low Grade ◽  
Chronic Hyperglycemia ◽  
Increased Risk

AbstractType 2 diabetes mellitus (T2DM) is a multifactorial chronic metabolic disease characterized by chronic hyperglycemia due to insulin resistance and a deficiency in insulin secretion. The global diabetes pandemic relates primarily to T2DM, which is the most prevalent form of diabetes, accounting for over 90% of all cases. Chronic low-grade inflammation, triggered by numerous risk factors, and the chronic activation of the immune system are prominent features of T2DM. Here we highlight the role of blood cells (platelets, and red and white blood cells) and vascular endothelial cells as drivers of systemic inflammation in T2DM. In addition, we discuss the role of microparticles (MPs) in systemic inflammation and hypercoagulation. Although once seen as inert by-products of cell activation or destruction, MPs are now considered to be a disseminated storage pool of bioactive effectors of thrombosis, inflammation, and vascular function. They have been identified to circulate at elevated levels in the bloodstream of individuals with increased risk of atherothrombosis or cardiovascular disease, two significant hallmark conditions of T2DM. There is also general evidence that MPs activate blood cells, express proinflammatory and coagulant effects, interact directly with cell receptors, and transfer biological material. MPs are considered major players in the pathogenesis of many systemic inflammatory diseases and may be potentially useful biomarkers of disease activity and may not only be of prognostic value but may act as novel therapeutic targets.

scholarly journals Triglyceride-containing lipoprotein sub-fractions and risk of coronary heart disease and stroke: A prospective analysis in 11,560 adults

2020 ◽  
Vol 27 (15) ◽  
pp. 1617-1626 ◽  
Author(s):  
Roshni Joshi ◽  
S Goya Wannamethee ◽  
Jorgen Engmann ◽  
Tom Gaunt ◽  
Deborah A Lawlor ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Odds Ratio ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Increased Risk ◽  
The Individual

Aims Elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cardiovascular disease; however, there is uncertainty about the role of total triglycerides and the individual triglyceride-containing lipoprotein sub-fractions. We measured 14 triglyceride-containing lipoprotein sub-fractions using nuclear magnetic resonance and examined associations with coronary heart disease and stroke. Methods Triglyceride-containing sub-fraction measures were available in 11,560 participants from the three UK cohorts free of coronary heart disease and stroke at baseline. Multivariable logistic regression was used to estimate the association of each sub-fraction with coronary heart disease and stroke expressed as the odds ratio per standard deviation increment in the corresponding measure. Results The 14 triglyceride-containing sub-fractions were positively correlated with one another and with total triglycerides, and inversely correlated with high-density lipoprotein cholesterol (HDL-C). Thirteen sub-fractions were positively associated with coronary heart disease (odds ratio in the range 1.12 to 1.22), with the effect estimates for coronary heart disease being comparable in subgroup analysis of participants with and without type 2 diabetes, and were attenuated after adjustment for HDL-C and LDL-C. There was no evidence for a clear association of any triglyceride lipoprotein sub-fraction with stroke. Conclusions Triglyceride sub-fractions are associated with increased risk of coronary heart disease but not stroke, with attenuation of effects on adjustment for HDL-C and LDL-C.

scholarly journals Nutrients and Immunometabolism: Role of Macrophage NLRP3

2020 ◽  
Vol 150 (7) ◽  
pp. 1693-1704
Author(s):  
Kate J Claycombe-Larson ◽  
Travis Alvine ◽  
Dayong Wu ◽  
Nishan S Kalupahana ◽  
Naima Moustaid-Moussa ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Tissue Cell ◽  
Cell Functions ◽  
Pyrin Domain ◽  
Increased Risk ◽  
Vital Cell ◽  
Cell Type Specific ◽  
Specific Regulation

ABSTRACT Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type–specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.

scholarly journals The Long and Short of It: The Role of Telomeres in Fetal Origins of Adult Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Stephanie E. Hallows ◽  
Timothy R. H. Regnault ◽  
Dean H. Betts
Keyword(s):  
Intrauterine Growth Restriction ◽  
The Body ◽  
Premature Aging ◽  
Fetal Origins ◽  
Maternal Malnutrition ◽  
Adult Disease ◽  
Increased Risk

Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.

The Challenge of Lipid Management in Patients with Diabetes or Other Endocrine Disorders

2010 ◽  
Vol 7 (2) ◽  
pp. 92
Author(s):  
Alberico L Catapano ◽  
Liliana Grigore ◽  
Angela Pirillo ◽  
◽  
◽  
...  
Keyword(s):  
Statin Therapy ◽  
Meta Analysis ◽  
Diabetic Patients ◽  
Endocrine Disorders ◽  
Lipid Management ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Associated Risk Factors

Diabetes increases the risk of developing cardiovascular disease (CVD), and several guidelines suggest that subjects with diabetes are at high risk of developing CVD. The increased risk can be attributed, at least in part, to associated risk factors, including hypertension and dyslipidaemia. The role of statins in primary and secondary prevention of CVD is well established, and the positive effect has been clearly demonstrated also in patients with type 2 diabetes. A number of studies have evaluated the effect of statin therapy on incident CVD and shown that statin therapy produces a great reduction in cardiovascular risk, but a recent meta-analysis revealed a slight increase in the risk of developing diabetes. Such risk is, however, low, especially when compared with the reduction in cardiovascular events and should not interfere with the choice of treating diabetic patients with a cholesterol-lowering therapy.

scholarly journals The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus

2021 ◽  
Author(s):  
Bertram Pitt ◽  
Gabriel Steg ◽  
Lawrence A. Leiter ◽  
Deepak L. Bhatt
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Relative Increase ◽  
Sodium Glucose Cotransporter ◽  
Increased Risk ◽  
Sglt2 Inhibition

Abstract Purpose In patients with type 2 diabetes mellitus (T2DM), both sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide receptor agonists (GLP-1 RAs) have demonstrated significant improvements in cardiovascular and kidney outcomes independent of their glycemic benefits. This paper will briefly compare the effect of SGLT2is and GLP-1 RAs to that of the SGLT1/2 inhibitor sotagliflozin on the incidence of myocardial infarction (MI) and stroke in patients with T2DM and further postulate mechanisms to account for these findings. Methods and Results Thus far, the results from SCORED and SOLOIST (trials studying the SGLT1/2 inhibitor sotagliflozin) suggest that an increase in SGLT1 inhibition when added to SGLT2 inhibition may contribute to reductions in MI and stroke in patients with T2DM. This benefit is beyond what SGLT2is alone can accomplish and at least similar to GLP-1 RAs but with the added benefit of a reduction in hospitalizations and urgent visits for HF. Larger and longer studies are required to confirm the effectiveness of SGLT1/SGLT2 inhibition in reducing MI and stroke in patients with T2DM and elucidate the mechanisms associated with this finding. Conclusions The role of SGLT1/2 inhibition as an addition to GLP-1 RAs in patients with and without T2DM at increased risk for MI and stroke requires further study. Regardless, the finding that a relative increase in SGLT1/2 inhibition reduces the risk of MI and stroke as well as hospitalizations and urgent visits for heart failure could improve quality of life and reduce the healthcare burden associated with T2DM.

scholarly journals Hypertriglyceridemia in Diabetes Mellitus: Implications for Pediatric Care

2018 ◽  
Vol 2 (6) ◽  
pp. 497-512 ◽  
Author(s):  
Jacob C Hartz ◽  
Sarah de Ferranti ◽  
Samuel Gidding
Keyword(s):  
Diabetes Mellitus ◽  
Children And Adolescents ◽  
Pediatric Care ◽  
Poor Control ◽  
Atherogenic Lipid Profile ◽  
Increased Risk ◽  
Atherogenic Lipid

Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). It is estimated that the risk of CVD in diabetes mellitus (DM) is 2 to 10 times higher than in the general population. Much of this increased risk is thought to be related to the development of an atherogenic lipid profile, in which hypertriglyceridemia is an essential component. Recent studies suggest that dyslipidemia may be present in children and adolescents with DM, particularly in T2DM and in association with poor control in T1DM. However, the role of hypertriglyceridemia in the development of future CVD in youth with DM is unclear, as data are scarce. In this review, we will evaluate the pathophysiology of atherogenic hypertriglyceridemia in DM, the evidence regarding an independent role of triglycerides in the development of CVD, and the treatment of hypertriglyceridemia in patients with DM, highlighting the potential relevance to children and the need for more data in children and adolescents to guide clinical practice.

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