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Metabolic syndrome: from the genetics to the pathophysiology

Published on Apr 1, 2011in Current Hypertension Reports3.606
· DOI :10.1007/s11906-010-0164-9
Silvia Sookoian37
Estimated H-index: 37
(UBA: University of Buenos Aires),
Carlos J. Pirola41
Estimated H-index: 41
(UBA: University of Buenos Aires)
Abstract
The metabolic syndrome (MS) constitutes a combination of underlying risk factors for an adverse outcome, cardiovascular disease. Thus, the clinical behavior of the MS can be regarded as a whole. Nevertheless, from a pathogenic point of view, understanding of the underlying mechanisms of each MS intermediate phenotype is far beyond their understanding as an integrative process. Systems biology introduces a new concept for revealing the pathogenesis of human disorders and suggests the presence of common physiologic processes and molecular networks influencing the risk of a disease. This paper shows a model of this concept to explain the genetic determinants of MS-associated phenotypes. Based on the hypothesis that common physiologic processes and molecular networks may influence the risk of MS disease components, we propose two systems-biology approaches: a gene enrichment analysis and the use of a protein-protein interaction network. Our results show that a network driven by many members of the nuclear receptor superfamily of proteins, including retinoid X receptor and farnesoid X receptor (FXR), may be implicated in the pathogenesis of the MS by its interactions at multiple levels of complexity with genes associated with metabolism, cell differentiation, and oxidative stress. In addition, we review two alternative genetic mechanisms that are gaining acceptance in the physiopathology of the MS: the regulation of transcriptional and post-transcriptional gene expression by microRNAs and epigenetic modifications such as DNA methylation.
  • References (37)
  • Citations (54)
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References37
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#1Hélène Duez (University of Lille Nord de France)H-Index: 32
#2Bart Staels (University of Lille Nord de France)H-Index: 136
Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep (fasting)/wake (feeding) cycles, and metabolic regulation display diurnal rhythms. The biological clock ensures proper metabolic alignment of energy substrate availability and processing. Studies in animals and humans highlight a strong link between circadian disorders and altered metabolic responses and cardiovascular events. Shift work, for instance, increases the risk to develop ...
51 CitationsSource
#1Silvia Sookoian (UBA: University of Buenos Aires)H-Index: 37
#2Tomas Fernández Gianotti (UBA: University of Buenos Aires)H-Index: 24
Last. Carlos J. Pirola (UBA: University of Buenos Aires)H-Index: 41
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Serotonergic neurotransmission and the master circadian CLOCK gene are physiological modulators of the circadian system. In addition, both are involved in the physiopathology of metabolic syndrome (MS). The authors sought to examine the potential effect of the gene-gene interaction between the functional 44-bp insertion/deletion polymorphism in the promoter region (serotonin-transporter-linked promoter region polymorphism or 5-HTTLPR) of the serotonin transporter gene (SLC6A4) and common variant...
21 CitationsSource
#1David Warde-Farley (U of T: University of Toronto)H-Index: 22
#2Sylva L. Donaldson (U of T: University of Toronto)H-Index: 9
Last. Quaid Morris (U of T: University of Toronto)H-Index: 52
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GeneMANIA (http://www.genemania.org) is a flexible, user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. Six organisms are currently supported (Arabidopsis thal...
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#1Katey J. Rayner (NYU: New York University)H-Index: 33
#2Yajaira Suárez (NYU: New York University)H-Index: 37
Last. Carlos Fernández-Hernando (NYU: New York University)H-Index: 48
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Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element–binding factor–2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate–binding cassette (ABC) transporter, ABCA1, thereby attenuating cholester...
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#1Carolina Gemma (UBA: University of Buenos Aires)H-Index: 20
#2Silvia Sookoian (UBA: University of Buenos Aires)H-Index: 37
Last. Carlos J. Pirola (UBA: University of Buenos Aires)H-Index: 41
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Abstract Purpose To explore whether DNA methylation of the mitochondrial transcription factor A ( TFAM) promoter is associated with insulin resistance in a sample of adolescents with features of metabolic syndrome. Methods The data and blood samples were collected from 122 adolescents out of a cross-sectional study of 934 high-school students. The population was divided into two groups: noninsulin resistance (NIR) and insulin resistance (IR). After bisulfite treatment of genomic DNA from periphe...
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#1Marcus E. Peter (U of C: University of Chicago)H-Index: 78
Micro(mi)RNAs are small noncoding RNAs that regulate expression of the majority of the genes in the genome at either the messenger RNA (mRNA) level (by degrading mRNA) or the protein level (by blocking translation). miRNAs are thought to be components of vast regulatory networks. Currently, the field is focused primarily on identifying novel targets of individual miRNAs. This focus is about to undergo a dramatic change. In a new paper by Wu et al. (2010) it is experimentally confirmed that multi...
156 CitationsSource
#1Silvia SookoianH-Index: 37
Last. Carlos J. PirolaH-Index: 41
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OBJECTIVE: To perform a two-stage study to explore the role of gene variants in the risk of insulin resistance and arterial hypertension. METHODS AND RESULTS: The selection of variants was performed by a first stage of in-silico analysis of the original genome-wide association data sets on genes involved in metabolic syndrome components, granted by the Diabetes Genetics Initiative and the Wellcome Trust Case-Control Consortium. We started by identifying single-nucleotide polymorphisms with a cut...
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#1Shengxu LiH-Index: 33
#2Jing Hua ZhaoH-Index: 78
Last. Ruth LoosH-Index: 117
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Background: Large-scale genome-wide association studies have identified 12 genetic loci that are robustly associated with body mass index (BMI). Objectives: We examined associations and compared effect sizes of these newly identified obesity susceptibility loci with various anthropometric traits and assessed their cumulative effects and predictive value for obesity risk. Design: We genotyped 12 single nucleotide polymorphisms (SNPs) from each locus in 20,431 individuals (age: 39-79 y) from the p...
161 CitationsSource
#1Silvia Sookoian (UBA: University of Buenos Aires)H-Index: 37
#2Carolina Gemma (UBA: University of Buenos Aires)H-Index: 20
Last. Carlos J. Pirola (UBA: University of Buenos Aires)H-Index: 41
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Abstract Background The nuclear receptor hepatocyte nuclear factor 4 α ( HNF4α ) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes. Aim To evaluate the influence of HNF4α polymorphisms across the entire locus on the occurrence of type 2 diabetes (T2D) by means of a meta-analysis. Methods We evaluated haplotype block structure of HNF4α variants owing to linkage disequilibrium (LD). From 1455 reports, we evaluated 21 observational studies. Results Six h...
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Although obesity, reduced physical activity, and aging increase susceptibility to type 2 diabetes, many people exposed to these risk factors do not develop the disease. Recent genome-wide association studies have identified a number of genetic variants that explain some of the interindividual variation in diabetes susceptibility (1–5). There is also a growing body of literature suggesting a role for epigenetic factors in the complex interplay between genes and the environment. Nevertheless, our ...
393 CitationsSource
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#1A. Marcos-Delgado (University of León)
#2E. López-García (UAM: Autonomous University of Madrid)
Last. Julia Wärnberg (RMIT: RMIT University)H-Index: 17
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Abstract Introduction and objectives Metabolic syndrome (MetS) is a combination of various cardiovascular risk factors with a major impact on morbidity and premature mortality. However, the impact of MetS on self-reported health-related quality of life (HRQoL) is unknown. This study evaluated the HRQoL in a Spanish adult population aged 55 years and older with MetS. Method A cross-sectional analysis was performed with baseline data from the PREDIMED-Plus multicentre randomized trial. The partici...
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#1Carlos J. Pirola (UBA: University of Buenos Aires)H-Index: 41
#2Silvia Sookoian (UBA: University of Buenos Aires)H-Index: 37
INTRODUCTION Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors - defined as stable and heritable changes in gene expression without changes in the DNA sequence - may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage. AREAS COVERED By using systems biology approaches, we review the main ...
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#1Yuxiang Huang (Southern Medical University)H-Index: 1
#2Li-Qin Zhao (Southern Medical University)H-Index: 2
Last. Hequn Zou (Southern Medical University)H-Index: 12
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Purpose. Metabolic syndrome (MetS) is associated with chronic stress. miR-18a-5p and miR-22-3p are two miRNAs which can target the glucocorticoid receptor. This study looked at the changes in metabolic parameters and the predictive value of the peripheral blood mononuclear cells (PBMCs) to stress-associated miRNA ratios as new indicators in subjects with and without MetS in southern China. Patients and Methods. There were 81 participants (39 with MetS and 42 without MetS) in this cross-sectional...
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Last. Sirichai Adisakwattana (Chula: Chulalongkorn University)H-Index: 26
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Abstract Riceberry rice (Oryza sativa L.), a new cross-breed from Hom Nin rice, a local non-glutinous purple rice, and Khoa Dawk Mali 105. The present study systematically assessed the effect of Riceberry rice extract (RBE) on the inhibition of key steps of carbohydrate and lipid digestion and absorption. The main anthocyanin identified in RBE was cyanidin-3-O-glucoside and peonidin-3-O-glucoside. In the step of carbohydrate digestion and absorption, RBE markedly inhibited intestinal maltase and...
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#1Ligita Ryliškytė (Vilnius University)H-Index: 12
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AbstractPurpose: The objective of this study was to assess predictive value of various arterial markers for cardiovascular (CV) events in patients with metabolic syndrome (MetS).Materials and methods: A longitudinal study with the follow-up period of 3.9 ± 1.7 years investigated 2728 middle-aged (53.9 ± 6.2 years old, 63% women) MetS subjects without overt CV disease. The study cohort was comprised of the participants of the Lithuanian High Cardiovascular Risk primary prevention program. The bas...
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#1Eun Kyung Choe (Seoul National University Hospital)H-Index: 10
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#1Yuxiang Huang (Southern Medical University)H-Index: 1
#2Yuxiang Yan (Capital Medical University)H-Index: 1
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Metabolic syndrome (MetS), which includes several clinical components such as abdominal obesity, insulin resistance (IR), dyslipidemia, microalbuminuria, hypertension, proinflammatory state, and oxidative stress (OS), has become a global epidemic health issue contributing to a high risk of type 2 diabetes mellitus (T2DM). In recent years, microRNAs (miRNAs), used as noninvasive biomarkers for diagnosis and therapy, have aroused global interest in complex processes in health and diseases, includi...
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Abstract Metabolic syndrome is the aggregation of cardiovascular risk factors that increases the risk of type 2 diabetes and cardiovascular diseases. Family and twin studies, heritability spectrum for its components and different prevalence among ethnicities, have provided genetic susceptibility to the metabolic syndrome. The investigations of genetic base for the disorder have recognized numerous chromosomes, various DNA polymorphisms in candidate genes and many gene variants, that are associat...
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Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin resistance, dyslipidemia, and central obesity. The low-density lipoprotein receptor-related protein 1 (LRP1—A member of the LDL receptor family) is an endocytic and signaling receptor that is expressed in ...
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