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Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?  [PDF]
Paola Dongiovanni,Luca Valenti
PPAR Research , 2013, DOI: 10.1155/2013/452061
Abstract: Nonalcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs), represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation. 1. Introduction Nonalcoholic fatty liver disease (NAFLD), a major cause of progressive liver disease, is defined by an increase in hepatic fat content not related to toxics and has a strong genetic component. As the peroxisome proliferator-activated receptors (PPARs) represent major regulators of lipid metabolism in the liver, a few studies have tested the hypothesis that genetic variants in these hormone receptors may influence the susceptibility to NAFLD, but with controversial results. In this paper, we provide an overview of the published evidence in the field, and a meta-analysis of the available results on the role of the Pro12Ala PPARγ single nucleotide polymorphism (SNP), the most studied genetic variant to date. As PPARs are also the target of several drugs under evaluation for the treatment of NAFLD, this evidence may lay the basis to design pharmacogenetic studies to assess the role of PPARs SNPs in predicting the response to drugs targeting these nuclear receptors. 2. Nonalcoholic Fatty Liver Disease (NAFLD) Liver fat deposition related to systemic insulin resistance (IR) defines NAFLD [1]. The acronym NAFLD defines a wide spectrum of liver disease ranging from simple uncomplicated hepatic fat accumulation in the
Non-Alcoholic Fatty Liver Disease: The Bile Acid-Activated Farnesoid X Receptor as an Emerging Treatment Target  [PDF]
Michael Fuchs
Journal of Lipids , 2012, DOI: 10.1155/2012/934396
Abstract: Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR) has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects. 1. Introduction One characteristic of our modern civilization is the easy and unlimited access to unhealthy and caloric dense food. A typical American diet furnishes the liver with ~20?g of fat each day, equivalent to one-half of the total triglyceride content of the liver. In combination with little need for physical activity due to technological advances, one consequence of our sedentary and excessive lifestyle is non-alcoholic fatty liver disease (NAFLD). NAFLD is a major health problem affecting up to 60 million Americans and evolving as the most common liver disease worldwide [1, 2]. This is several-fold higher than other common chronic liver diseases such as hepatitis C and alcohol-related liver disease. While the majority of subjects with NAFLD are obese, the condition can occur in the absence of obesity or other features of the metabolic syndrome. In patients with diabetes and morbid obesity the prevalence of NAFLD has been shown to be as high as 62% and 96%, respectively [3, 4]. The earliest stage of NAFLD is fatty liver that is defined as the presence of cytoplasmic triglyceride droplets in more than 5% of hepatocytes [5]. Although often self-limited, in 12–40% it can progress to non-alcoholic steatohepatitis (NASH) [6]. NASH is distinguished from simple fatty liver by the presence of hepatocyte injury such as hepatocyte ballooning and apoptosis, an inflammatory infiltrate, and/or collagen deposition. Over a time period of 10–15 years, 15% of patients with NASH
Nuclear Receptors in Nonalcoholic Fatty Liver Disease  [PDF]
Jorge A. López-Velázquez,Luis D. Carrillo-Córdova,Norberto C. Chávez-Tapia,Misael Uribe,Nahum Méndez-Sánchez
Journal of Lipids , 2012, DOI: 10.1155/2012/139875
Abstract: Nuclear receptors comprise a superfamily of ligand-activated transcription factors that are involved in important aspects of hepatic physiology and pathophysiology. There are about 48 nuclear receptors in the human. These nuclear receptors are regulators of many hepatic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, drug detoxification, inflammation, regeneration, fibrosis, and tumor formation. Some of these receptors are sensitive to the levels of molecules that control lipid metabolism including fatty acids, oxysterols, and lipophilic molecules. These receptors direct such molecules to the transcriptional networks and may play roles in the pathogenesis and treatment of nonalcoholic fatty liver disease. Understanding the mechanisms underlying the involvement of nuclear receptors in the pathogenesis of nonalcoholic fatty liver disease may offer targets for the development of new treatments for this liver disease. 1. Introduction Liver diseases are a serious problem throughout the world. In Mexico, since 2000, cirrhosis and other chronic liver diseases have become among the main causes of mortality [1]. The incidence and prevalence of liver diseases are increasing along with changes in lifestyle and population aging, and these diseases were responsible for 20,941 deaths in 2007 [2]. In Mexico, the incidence of metabolic syndrome is also increasing. The metabolic syndrome has recently been associated with nonalcoholic fatty liver disease (NAFLD), and about 90% of patients with NAFLD have more than one feature of the metabolic syndrome [3]. The severity of NAFLD is one factor contributing to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma [4, 5]. The growing obesity epidemic requires a better understanding of the genetic networks and signal transduction pathways that regulate the pathogenesis of these conditions. A clear definition of the mechanisms responsible for metabolic control may provide new knowledge for the development of new drugs, with novel mechanisms of action, for the treatment of chronic liver diseases. The ability of individual nuclear receptors (NRs) to regulate multiple genetic networks in different tissues and their own ligands may represent a new class of potential drugs targets. To elucidate the challenges involved in developing such drugs, this paper focuses on the role of hepatic NRs in lipid metabolism and the possible effects on the physiopathology of NAFLD. 2. Nonalcoholic Fatty Liver Disease NAFLD is defined by the accumulation of triglycerides in
Nuclear Receptor Small Heterodimer Partner in Apoptosis Signaling and Liver Cancer  [PDF]
Yuxia Zhang,Li Wang
Cancers , 2011, DOI: 10.3390/cancers3010198
Abstract: Small heterodimer partner ( SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel pro-oncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment.
Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease  [cached]
Yu-Yuan Li
World Journal of Gastroenterology , 2012, DOI: 10.3748/wjg.v18.i45.6546
Abstract: Nonalcoholic fatty liver disease (NAFLD) is common worldwide. The importance of genetic and epigenetic changes in etiology and pathogenesis of NAFLD has been increasingly recognized. However, the exact mechanism is largely unknown. A large number of single nucleotide polymorphisms (SNPs) related to NAFLD has been documented by candidate gene studies (CGSs). Among these genes, peroxisome proliferatoractivated receptor-γ, adiponectin, leptin and tumor necrosis factor-α were frequently reported. Since the introduction of genome-wide association studies (GWASs), there have been significant advances in our understanding of genomic variations of NAFLD. Patatin-like phospholipase domain containing family member A3 (PNPLA3, SNP rs738409, encoding I148M), also termed adiponutrin, has caught most attention. The evidence that PNPLA3 is associated with increased hepatic fat levels and hepatic inflammation has been validated by a series of studies. Epigenetic modification refers to phenotypic changes caused by an adaptive mechanism unrelated to alteration of primary DNA sequences. Epigenetic regulation mainly includes microRNAs (miRs), DNA methylation, histone modifications and ubiquitination, among which miRs are studied most extensively. miRs are small natural single stranded RNA molecules regulating mRNA degradation or translation inhibition, subsequently altering protein expression of target genes. The miR-122, a highly abundant miR accounting for nearly 70% of all miRs in the liver, is significantly under-expressed in NAFLD subjects. Inhibition of miR-122 with an antisense oligonucleotide results in decreased mRNA expression of lipogenic genes and improvement of liver steatosis. The investigation into epigenetic involvement in NAFLD pathogenesis is just at the beginning and needs to be refined. This review summarizes the roles of genetics and epigenetics in the development of NAFLD. The progress made in this field may provide novel diagnostic biomarkers and therapeutic targets for NAFLD management.
Interleukin-4 receptor alpha gene variants and allergic disease
Ian P Hall
Respiratory Research , 2000, DOI: 10.1186/rr3
Abstract: Several genome-wide screens have now been performed in different populations, looking for susceptibility genes for asthma and allergic disease. In general, the results of these genome screens have been somewhat disappointing in that, although chromosomal regions showing linkage have been identified, the strength of linkage at any given site has been inconsistent. These data suggest that a number of genes of moderate effect rather than a small number of genes with marked effects contribute to the genetic basis of allergic disease.To try to dissect out the important candidate genes that contribute to the risk of developing asthma or its important sub-phenotypes, several groups have concentrated on strong candidate genes that map to known susceptibility loci for asthma and atopy. Several such candidates have been identified (Table 1), including the gene for interleukin-4 receptor α (IL-4Rα), which is situated on chromosome 16p and is known to contain a number of polymorphisms. The recent paper from Carole Ober and colleagues [1] provides important information on the potential relevance of IL-4Rα gene variants in determining the risk of developing atopic disease.The IL-4Rα subunit forms part of the signalling complex for IL-4 itself but also serves as the α chain of the IL-13 receptor. Both IL-4 and IL-13 themselves have been implicated as potential candidate genes in the development of asthma, both being present in the TH2 cytokine locus on chromosome 5q23-31 [2]. Both IL-4 and IL-13 have overlapping functions, including mediating isotype switching to IgE synthesis.Several previous studies have suggested association and/or linkage between IL-4Rα gene variants and allergic disease, although not all studies have been positive. Mitsuyasu et al [3] reported the Ile50 allele of the IL-4Rα to be associated with atopic asthma, whereas Kruse et al [4] reported an association between the Pro478 and Arg551 alleles and low IgE levels. Hershey et al [5] reported an association bet
The Liver X Receptor in Correlation with Other Nuclear Receptors in Spontaneous and Recurrent Abortions  [PDF]
Julia Knabl,Aurelia Pestka,Rebecca Hüttenbrenner,Torsten Pl?sch,Regina Ensenauer,Lena Welbergen,Stefan Hutter,Maria Günthner-Biller,Udo Jeschke
PPAR Research , 2013, DOI: 10.1155/2013/575604
Abstract: The liver X receptors (LXRs) have been shown to be crucially involved in maternal-fetal cholesterol transport and placentation. The aim of this study was to investigate the expression pattern and frequency of LXR under normal physiological circumstances and in spontaneous abortion and/or recurrent miscarriage. A total of 29 (12 physiologic pregnancies/10 spontaneous abortions/7 recurrent miscarriages) human pregnancies in first trimester were analysed for LXR expression. Expression changes were evaluated by immunohistochemistry for receptor and quantitative RT-PCR (TaqMan) was performed to determine the level of LXR mRNA expression. We also stained for RXRα and PPARγ as possible heterodimers of LXR. LXR expression was downregulated in the syncytiotrophoblast of spontaneous abortion placentas compared to normal pregnancy. In recurrent miscarriage there was a trend for a downregulation. Decidua showed an even stronger downregulation in both groups. In the syncytiotrophoblast we found a positive correlation for the combination of LXR/PPARγ in abortions and a negative correlation for LXR/RXRα. In addition, double-immunofluorescence staining showed that LXR as well as RXRα and PPARγ are expressed by the extravillous trophoblast. Finally, RXRα and LXR showed coexpression in the same extravillous trophoblast cells. To conclude, our data show that LXR expression is decreased in miscarriage. 1. Introduction Multiple regulatory mechanisms (e.g., immunologic, endocrine, and metabolic) are involved in the success of human pregnancy and disturbances in any of these processes can lead to fetal loss. However, 25–50% of reproductive-aged women experience one or more miscarriages. Furthermore, 1–3% of women during childbearing years suffer from recurrent miscarriage (RM), the occurrence of three or more consecutive spontaneous miscarriages regardless of previous live births [1, 2]. In nearly 50% of affected patients, the cause of RM remains unknown and investigations on underlying processes are mandatory [1]. Previous studies of our group showed that nuclear receptors in general are involved in this process. The nuclear retinoid X receptor (RXR)—which is involved in cell proliferation, cell differentiation, and organogenesis [3]—is upregulated in recurrent miscarriages [4]. RXR is a key player of the receptor family, due to its ability to form heterodimers with other nuclear receptors. Heterodimer partners are, for example, peroxisome proliferator-activated receptor (PPAR), thyroid hormone receptor (TR), and liver X receptor (LXR) [5–7]. PPARγ expression and role are
Coronary heart disease: Significance of liver X receptor α genomics  [cached]
Vivek Priy Dave,Deepak Kaul
World Journal of Cardiology , 2010,
Abstract: Crosstalk between lipid peroxidation and inflammation is known to be a pathognomonic feature for the development of coronary heart disease (CHD). In this regard ligand activated liver X receptor (LXR)-α has emerged as a key molecular switch by its inherent ability to modulate an array of genes involved in these two fundamental cellular processes. In addition, LXR-α has also been found to play a role in hepatic lipogenesis and innate immunity. Although several lines of evidence in experimental model systems have established the atheroprotective nature of LXR-α, human subjects have been reported to possess a paradoxical situation in which increased blood cellular LXR-α gene expression is always accompanied by increased coronary occlusion. This apparent paradox was resolved recently by the finding that CHD patients possess a deregulated LXR-α transcriptome due to impaired ligand-receptor interaction. This blood cellular mutated LXR-α gene expression correlated specifically with the extent of coronary occlusion and hence need is felt to devise new synthetic ligands that could restore the function of this mutated LXR-α protein in order to modulate genes involved in reverse cholesterol transport and suppression of the inflammatory response leading to the effective treatment of CHD.
Cannabinoid Receptor Type 2 Functional Variant Influences Liver Damage in Children with Non-Alcoholic Fatty Liver Disease  [PDF]
Francesca Rossi, Giulia Bellini, Anna Alisi, Arianna Alterio, Sabatino Maione, Laura Perrone, Franco Locatelli, Emanuele Miraglia del Giudice, Valerio Nobili
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042259
Abstract: Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis. Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD. CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage. We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02). Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.
Analysis of nuclear glucocorticoid receptor–DNA interaction in aged rat liver
Journal of the Serbian Chemical Society , 2005,
Abstract: In order to contribute to the understanding of mechanisms by which regulatory proteins recognize genetic information stored in DNA, analyses of their interaction with specific nucleotides are usually performed. In this study, the electrophoretic mobility shift assay (EMSA) was applied to analyze the interaction of nuclear proteins from the liver of rats of different age i.e., young (3-month-old), middle-aged (12-month-old) and aged (24-month-old), with radioactively labelled synthetic oligonucleotide analogues, corresponding to GRE. The levels of GRE binding activity were assessed by quantitative densitometric scanning of the autoradiograms. The results showed statistically significant decreasing values of up to 78% and 49% in middle aged and old animals, respectively, compared to young animals (p < 0.05). The specificity of the nuclear proteins-GRE interaction was demonstrated by competition experiments with unlabelled GRE. In a supershift assay, using the antibody BuGR2, it was shown that the GR proteins present in nuclear extracts have a high affinity for the GRE probe. The stabilities of the protein-DNA complexes were analysed and it was concluded that they changed during ageing.
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