scholarly journals Promethin Is a Conserved Seipin Partner Protein

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 268 ◽  
Author(s):  
Inês Castro ◽  
Michal Eisenberg-Bord ◽  
Elisa Persiani ◽  
Justin Rochford ◽  
Maya Schuldiner ◽  
...  
Keyword(s):  
Human Health ◽  
Lipid Droplet ◽  
Storage Disease ◽  
Human Protein ◽  
Partner Protein ◽  
Evolutionarily Conserved ◽  
Key Factor ◽  
Related Proteins

Seipin (BSCL2/SPG17) is a key factor in lipid droplet (LD) biology, and its dysfunction results in severe pathologies, including the fat storage disease Berardinelli-Seip congenital lipodystrophy type 2, as well as several neurological seipinopathies. Despite its importance for human health, the molecular role of seipin is still enigmatic. Seipin is evolutionarily conserved from yeast to humans. In yeast, seipin was recently found to cooperate with the lipid droplet organization (LDO) proteins, Ldo16 and Ldo45, two structurally-related proteins involved in LD function and identity that display remote homology to the human protein promethin/TMEM159. In this study, we show that promethin is indeed an LD-associated protein that forms a complex with seipin, and its localization to the LD surface can be modulated by seipin expression levels. We thus identify promethin as a novel seipin partner protein.

scholarly journals Genes and Diet in the Prevention of Chronic Diseases in Future Generations

2020 ◽  
Vol 21 (7) ◽  
pp. 2633 ◽  
Author(s):  
Marica Franzago ◽  
Daniele Santurbano ◽  
Ester Vitacolonna ◽  
Liborio Stuppia
Keyword(s):  
Human Health ◽  
Dietary Intervention ◽  
Nutrient Requirements ◽  
Metabolic Disturbances ◽  
Transgenerational Transmission ◽  
Key Factor ◽  
Dietary Components ◽  
Diabetes Gestational

Nutrition is a modifiable key factor that is able to interact with both the genome and epigenome to influence human health and fertility. In particular, specific genetic variants can influence the response to dietary components and nutrient requirements, and conversely, the diet itself is able to modulate gene expression. In this context and the era of precision medicine, nutrigenetic and nutrigenomic studies offer significant opportunities to improve the prevention of metabolic disturbances, such as Type 2 diabetes, gestational diabetes, hypertension, and cardiovascular diseases, even with transgenerational effects. The present review takes into account the interactions between diet, genes and human health, and provides an overview of the role of nutrigenetics, nutrigenomics and epigenetics in the prevention of non-communicable diseases. Moreover, we focus our attention on the mechanism of intergenerational or transgenerational transmission of the susceptibility to metabolic disturbances, and underline that the reversibility of epigenetic modifications through dietary intervention could counteract perturbations induced by lifestyle and environmental factors.

scholarly journals SEIPIN: A Key Factor for Nuclear Lipid Droplet Generation and Lipid Homeostasis

2020 ◽  
Vol 21 (21) ◽  
pp. 8208
Author(s):  
Yi Jin ◽  
Yanjie Tan ◽  
Pengxiang Zhao ◽  
Zhuqing Ren
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Normal Cell ◽  
Single Layer ◽  
Lipid Homeostasis ◽  
Cell Physiology ◽  
Phospholipid Membrane ◽  
Key Factor

Lipid homeostasis is essential for normal cell physiology. Generally, lipids are stored in a lipid droplet (LD), a ubiquitous organelle consisting of a neutral lipid core and a single layer of phospholipid membrane. It is thought that LDs are generated from the endoplasmic reticulum and then released into the cytosol. Recent studies indicate that LDs can exist in the nucleus, where they play an important role in the maintenance of cell phospholipid homeostasis. However, the details of nuclear lipid droplet (nLD) generation have not yet been clearly characterized. SEIPIN is a nonenzymatic protein encoded by the Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) gene. It is associated with lipodystrophy diseases. Many recent studies have indicated that SEIPIN is essential for LDs generation. Here, we review much of this research in an attempt to explain the role of SEIPIN in nLD generation. From an integrative perspective, we conclude by proposing a theoretical model to explain how SEIPIN might participate in maintaining homeostasis of lipid metabolism.

scholarly journals Focus on the Role of NLRP3 Inflammasome in Diseases

2020 ◽  
Vol 21 (12) ◽  
pp. 4223 ◽  
Author(s):  
Roberta Fusco ◽  
Rosalba Siracusa ◽  
Tiziana Genovese ◽  
Salvatore Cuzzocrea ◽  
Rosanna Di Paola
Keyword(s):  
Immune System ◽  
Nlrp3 Inflammasome ◽  
Neurologic Disorders ◽  
Evolutionarily Conserved ◽  
The Family ◽  
Bowel Diseases ◽  
Protective Reaction ◽  
Inflammatory Bowel

Inflammation is a protective reaction activated in response to detrimental stimuli, such as dead cells, irritants or pathogens, by the evolutionarily conserved immune system and is regulated by the host. The inflammasomes are recognized as innate immune system sensors and receptors that manage the activation of caspase-1 and stimulate inflammation response. They have been associated with several inflammatory disorders. The NLRP3 inflammasome is the most well characterized. It is so called because NLRP3 belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent evidence has greatly improved our understanding of the mechanisms by which the NLRP3 inflammasome is activated. Additionally, increasing data in animal models, supported by human studies, strongly implicate the involvement of the inflammasome in the initiation or progression of disorders with a high impact on public health, such as metabolic pathologies (obesity, type 2 diabetes, atherosclerosis), cardiovascular diseases (ischemic and non-ischemic heart disease), inflammatory issues (liver diseases, inflammatory bowel diseases, gut microbiome, rheumatoid arthritis) and neurologic disorders (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurological disorders), compared to other molecular platforms. This review will provide a focus on the available knowledge about the NLRP3 inflammasome role in these pathologies and describe the balance between the activation of the harmful and beneficial inflammasome so that new therapies can be created for patients with these diseases.

scholarly journals Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes

2021 ◽  
Author(s):  
Verónica Hurtado-Carneiro ◽  
Ana Pérez-García ◽  
Elvira Álvarez ◽  
Carmen Sanz
Keyword(s):  
Type 2 Diabetes ◽  
Nutrient Availability ◽  
Energy Demand ◽  
Metabolic Response ◽  
Whole Body ◽  
Key Factor ◽  
Control Food ◽  
Control Food Intake

Cell survival depends on the constant challenge to match energy demands with nutrient availability. This process is mediated through a highly conserved network of metabolic fuel sensors that orchestrate both a cellular and whole-body energy balance. A mismatch between cellular energy demand and nutrient availability is a key factor in the development of type 2 diabetes, obesity, metabolic syndrome, and other associated pathologies; thus, understanding the fundamental mechanisms by which cells detect nutrient availability and energy demand may lead to the development of new treatments. This chapter reviews the role of the sensor PASK (protein kinase with PAS domain), analyzing its role in the mechanisms of adaptation to nutrient availability and the metabolic response in different organs (liver, hypothalamus) actively cooperating to control food intake, maintain glycaemia homeostasis, and prevent insulin resistance and weight gain.

scholarly journals Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Pierre-Alexandre Just ◽  
Sara Charawi ◽  
Raphaël G. P. Denis ◽  
Mathilde Savall ◽  
Massiré Traore ◽  
...  
Keyword(s):  
Amino Acid ◽  
Glucose Production ◽  
Whole Body ◽  
Postprandial Period ◽  
Key Factor ◽  
Liver Kinase B1 ◽  
Whole Body Metabolism ◽  
Specific Deletion

AbstractExcessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.

scholarly journals The role of adipokines in β-cell failure of type 2 diabetes

2012 ◽  
Vol 216 (1) ◽  
pp. T37-T45 ◽  
Author(s):  
Simon J Dunmore ◽  
James E P Brown
Keyword(s):  
Type 2 Diabetes ◽  
Β Cells ◽  
Β Cell ◽  
Beneficial Effects ◽  
Published Evidence ◽  
Key Factor ◽  
Excessive Adiposity ◽  
Factor Α

β-Cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review, we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of β-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, tumour necrosis factor α, resistin, visfatin, dipeptidyl peptidase IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to β-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines, which act on the β-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on β-cells.

scholarly journals MicroRNA-92a negatively regulates neurofibromin 2 and inhibits its tumor suppressive function

2018 ◽  
Author(s):  
Krizelle Mae M. Alcantara ◽  
Reynaldo L. Garcia
Keyword(s):  
Neurofibromatosis Type ◽  
Apoptosis Resistance ◽  
Lung Cancers ◽  
Actin Organization ◽  
Protein Levels ◽  
Evolutionarily Conserved ◽  
Tumor Suppressive Function ◽  
Hct116 Cells

ABSTRACTInactivation of the tumor suppressor Merlin leads to the development of benign nervous system tumors of neurofibromatosis type 2. Merlin deficiency is also observed in human malignancies including colorectal and lung cancers. Causes of Merlin inactivation include deleterious mutations in the encoding neurofibromin 2 gene (NF2) and aberrant Merlin proteasomal degradation. Here, we show that NF2 is also regulated by microRNAs (miRNAs) through interaction with evolutionarily conserved miRNA response elements (MREs) within its 3’-untranslated region (3‘UTR). Dual luciferase assays in HCT116 and A549 show downregulation of wild type NF2 by miR-92a via its 3’UTR but not NF2-3’UTR with mutated MRE. HCT116 cells transfected with miR-92a show significant downregulation of endogenous NF2 mRNA and protein levels, which were rescued by co-transfection of a target protector oligonucelotide specific for the miR-92a binding site within NF2-3’UTR. MiR-92a overexpression in HCT116 and A549 resulted in increased migration and proliferation, apoptosis resistance, and altered F-actin organization compared to controls. This study provides functional proof of the unappreciated role of miRNAs in NF2 regulation and tumor progression.

Abstract 441: Role of the Mitochondrial Translocator Protein (TSPO) in the Proarrhythmic Vulnerability of the Diabetic Heart

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jun Hu ◽  
Won-Joon Koh ◽  
Chaoqin Xie ◽  
Fadi G Akar
Keyword(s):  
Anion Channel ◽  
Mitochondrial Pathway ◽  
Translocator Protein ◽  
Diabetic Heart ◽  
Key Factor ◽  
Ros Scavenger ◽  
Zdf Rats ◽  
Tspo Expression

In structurally normal hearts, inhibition of the mitochondrial translocator protein (TSPO) prevents ROS-mediated proarrhythmia. Whether and how TSPO modulates electrophysiological (EP) function of diabetic hearts, in which classically cardioprotective pathways are impaired, is unknown. We determined the EP effects of TSPO activation & inhibition in a rat model of type 2 diabetes mellitus (t2DM) and studied the mitochondrial pathway underlying TSPO-related proarrhythmia. Methods: TSPO expression & function were determined in Zucker Diabetic Fatty (ZDF) rats with established t2DM (N=16) compared to controls (ctrl, N=15). Optical mapping was performed before & after challenge of hearts with ischemia for 12 min followed by reperfusion. Hearts underwent TSPO activation (FGIN 4.6uM, N=10), blockade (DZP 64uM, N=7) or no treatment (N=14). Dependence of TSPO-related proarrhythmia on ROS and on the PTP a target of TSPO were also determined. Results: t2DM hearts exhibited markedly increased TSPO expression (mRNA & protein) compared to ctrl. TSPO activation did not alter EP properties at baseline in ctrl or t2DM. In contrast TSPO activation accelerated action potential (AP) shortening during ischemia in t2DM but not ctrl hearts. Following 8 min of ischemia, FGIN-mediated AP shortening was 2X greater in t2DM compared to ctrl (p=0.008). FGIN-treated t2DM (5/7) but not ctrl (0/5) hearts exhibited VT by 12min of ischemia (p=0.027). AP shortening and VT in FGIN-treated t2DM hearts were not prevented by the PTP blocker Cyclosporin A but rather by the ROS scavenger EUK implicating the inner membrane anion channel in the proarrhythmic activity of TSPO. Upon reperfusion, TSPO activation with FGIN caused VF in 100% of ctrl & t2DM hearts compared to ~50% of untreated hearts. DZP prolonged the AP in t2DM (by 53% p<0.01) but not ctrl (p=0.14) hearts consistent with heightened sensitivity of t2DM to TSPO ligands. DZP blunted AP shortening during ischemia and prevented VF upon reperfusion in ctrl and t2DM hearts. Conclusion: t2DM hearts exhibit heightened sensitivity to TSPO ligands. TSPO upregulation may be a key factor in the proarrhythmic vulnerability of the diabetic heart. The cardioprotective efficacy of TSPO inhibition against arrhythmias is preserved in t2DM.

scholarly journals Biological significance of a universally conserved transcription mediator in metazoan developmental signaling pathways

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3095-3104 ◽  
Author(s):  
Jae Young Kwon ◽  
Junho Lee
Keyword(s):  
Signaling Pathways ◽  
Biological Significance ◽  
Genetic Mutation ◽  
Ras Pathway ◽  
C Elegans ◽  
Physical Maps ◽  
Evolutionarily Conserved ◽  
Related Proteins

Transcription mediators are known to be required for regulated transcription in yeast and higher eukaryotes. However, little is known about the specific roles of mediators in vivo during development. In this report, we have characterized the biological functions of the C. elegans genemed-6, which is the homolog of the yeast mediator med-6. We first identified a genetic mutation in the med-6 gene by comparing genetic and physical maps and determining the molecular lesion. Next, we demonstrated that med-6 plays an important role in metazoan development by regulating the transcription of genes in evolutionarily conserved signaling pathways. We showed that med-6 is involved in the transcription of genes of the Ras pathway by showing that med-6 RNAi suppressed phenotypes associated with gain-of-function alleles oflet-23 and let-60, and enhanced those associated with a reduction-of-function allele of lin-3. We also found thatmed-6 is involved in male ray development, which is partly mediated by the Wnt pathway. As MED-6 is universally conserved, including in yeast, and the mediator-related proteins that function in vulval and male ray development are metazoan specific, our results suggest the role of med-6 as a point of convergence where signals transmitted through metazoan-specific mediator-related proteins meet. In addition, RNAi experiments inrde-1 background showed that maternal and zygotic med-6activities have distinct roles in development.

scholarly journals Novel approach to pathophysiology of type 2 diabetes mellitus

2013 ◽  
Vol 16 (4) ◽  
pp. 49-51
Author(s):  
Emil' Kopeevich Mukhamedzhanov ◽  
Oleg Viktorovich Esyrev
Keyword(s):  
Diabetes Mellitus ◽  
Protein Metabolism ◽  
Metabolic Pathways ◽  
Energy Homeostasis ◽  
Insulin Signalling ◽  
Carbon Chain ◽  
Novel Approach ◽  
Key Factor

In this paper, we present a model of interplay between protein, lipid and carbohydrate metabolic pathways with regard to the carbon chain transporting systems, as well as generation and consumption of energy. This model elucidates the role of protein metabolism in the impairment of glucose tolerance during the absorption period. We also discuss the effects on energy homeostasis exercised by cytokines via mTOR pathway (the key factor of insulin signalling) considering the phenomenon of insulin resistance.

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