Effects of Perilipin (PLIN) Gene Variation on Metabolic Syndrome Risk and Weight Loss in Obese Children and Adolescents

Deram, Sophie; Nicolau, Carla Marques; Pérez-Martínez, Pablo; Guazzelli, Isabel; Halpern, Alfredo; Wajchenberg, B. L.; Ordovas, José M.; Villares, S M

doi:10.1210/jc.2008-0947

Cited by 41 publications

(43 citation statements)

References 29 publications

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“…Consistent with the increased rates of lipolysis, humans with this polymorphism tend to have reduced body weight and body fat mass (106,110). PLIN1 polymorphisms have also been suggested to affect the ability to lose weight on a diet (101,103), as well as the metabolic response to exercise (111). More work is needed to confirm and extend these observations among different human populations.…”

Section: Role Of Cide/plin1 In Obese Animals and Humansmentioning

confidence: 93%

The role of lipid droplets in metabolic disease in rodents and humans

Coleman²,

et al. 2011

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Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease. Overview of lipid dropletsLipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role they play in health and disease. LDs regulate the storage and hydrolysis of neutral lipids, including triacylglycerol (TAG) and/or cholesterol esters. For example, adipocytes, the major reservoir of TAG in the body, store their TAG within LDs, and TAG storage in adipocytes is increased in obese animals and humans. The rates of adipocyte lipolysis in many obese individuals are constitutively increased, resulting in elevated levels of circulating fatty acids, which may be stored as TAG in LDs within skeletal muscle and liver. Both local and circulating free fatty acids are thought to be important etiologic agents in the development of insulin resistance, hyperlipidemia, inflammation, and hepatic steatosis (1-3). In this article, we will briefly review the basic characteristics of LDs and then focus on our present knowledge of the current view of the role of LDs in metabolic disease.Cells have developed the capacity to store fatty acids as neutral lipids within LDs for several reasons. An important role of LDs in adipocytes is to store fatty acids as TAG to serve as a reservoir of energetic substrates that can be released when food is scarce. The detrimental effects associated with excess fatty acid entry into cells are often termed "lipotoxicity." Cells protect themselves from these effects by either oxidizing the fatty acids or sequestering them as TAG within LDs. Consistent with this hypothesis, activation of PPARα, which increases the expression of genes that encode oxidative proteins, also increases the expression of LDs and LD-associated proteins (4, 5). PPARγ and PPARδ, along with other transcription factors, can also promote droplet formation (4, 6). As noted above, when fatty acids exceed the oxidative capacity of cells, they not only enhance LD formation, but may also induce apoptosis. An example of the protection LD formation provides was demonstrated in an experiment in which exogenous oleic acid added to fibroblasts deficient in diacylglycerol acyltransferase 1 (DGAT1) promoted lipotoxic cell death. Expression of DGAT1, the terminal step in TAG synthesis, in fibroblasts channeled exces...

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Section: Role Of Cide/plin1 In Obese Animals and Humansmentioning

confidence: 93%

The role of lipid droplets in metabolic disease in rodents and humans

Coleman²,

et al. 2011

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“…The transcript of this molecule not only significantly correlated with FA, as described above, but was also cis -and trans -regulated. Another node within the network is the tumor necrosis factor (TNF) interacting with GSTT1, PLIN4, ANXA5, SOD2, VTI1B, and SLC12A1, some of which were previously associated with fat traits in human ( 47,48 ). Perilipins (PLIN) are proteins localized at the surface of the lipid droplets in adipocytes, steroid-producing cells, and play a key role in the cellular regulation of triglyceride deposition and mobilization ( 49 ).…”

Section: Whole-genome Association Analyses For Abundance Of Transcripmentioning

confidence: 99%

“…Perilipins (PLIN) are proteins localized at the surface of the lipid droplets in adipocytes, steroid-producing cells, and play a key role in the cellular regulation of triglyceride deposition and mobilization ( 49 ). PLIN polymorphisms have been associated with obesity-related phenotypes ( 47,50 ). Mitochondrial superoxide dismutase-2 (SOD-2) is an endogenous anti-oxidant enzyme.…”

Section: Whole-genome Association Analyses For Abundance Of Transcripmentioning

confidence: 99%

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

Ponsuksili

Muráni

Brand

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org lated to body composition, leanness, and obesity. Traits related to fatness are important not only as economic factors in pork production but also because of their association with serious diseases in humans ( 1, 2 ). Pigs share many similarities with humans in physiology and genomes and, therefore, provide a good model to study the genetic determination of complex traits ( 3 ). The study of a porcine model is benefi cial because a number of fatness traits (e.g., "fat area") can be determined quantitatively with great accuracy and reproducibility post mortem, and RNA samples are available for transcriptomic approaches. In humans, indices for obesity are obtained intra vitam (i.e., body mass index or body fat percentage are estimated based on statistical models of measures of near-infrared interactance, body average density measurement, bioelectrical impedance analysis, or anthropometric methods) ( 4 ).Functional genomics provides an insight into the molecular processes underlying phenotypic differences. The analysis of trait-correlated expression levels reveals genes belonging to pathways or networks relevant for the control of quantitative traits. However, holistic expression profi ling does not often discriminate differential expression of the genes as either an effect or a cause of variation.Genome-wide association studies (GWAS) in large natural populations of unrelated individuals have resulted in the association of many genes with complex traits (http:// www. genome.gov/gwastudies). Unfortunately, for a conAbstract Traits related to fatness, important as economic factors in pork production, are associated with serious diseases in humans. Genetical genomics is a useful approach for studying the effects of genetic variation at the molecular level in biological systems. Here we applied a whole-genome association analysis to hepatic gene expression traits, focusing on transcripts with expression levels that correlated with fatness traits in a porcine model. A total of 150 crossbred pigs [Pietrain×(German Large White × German Landrace)] were studied for transcript levels in the liver. The 24K Affymetrix expression microarrays and 60K Illumina single nucleotide polymorphism (SNP) chips were used for genotyping. A total of 663 genes, whose expression signifi cantly correlated with the trait "fat area," were analyzed for enrichment of functional annotation groups as defi ned in the Ingenuity Pathways Knowledge Base (IPKB). Genes involved in metabolism of various macromolecules and nutrients as well as functions related to dynamic cellular processes correlated with fatness traits. Regions affecting the transcription levels of these genes were mapped and revealed 4,727 expression quantitative trait loci (eQTL) at P < 10 The metabolic activities of the liver are essential for providing fuel to the peripheral organs. Most components absorbed by the intestine pass through the liver, which enables it to regulate the levels of many metabolites in the blood. Storage, ...

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“…Recent studies have investigated human perilipin expression ( 20,21,23 ). Several groups described the correlations between perilipin expression in adipose tissue or perilipin gene haplotype and gender, obesity, and glucose and lipid metabolism (24)(25)(26). To date, almost all published studies investigating the molecular mechanism of perilipin have focused on mouse perilipin ( 5,9,(27)(28)(29).…”

Section: Measures Of Glucose and Insulin Tolerancementioning

confidence: 99%

Perilipin overexpression in mice protects against diet-induced obesity

Miyoshi

Souza

Endo

et al. 2010

Journal of Lipid Research

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Journal of Lipid ResearchObesity is associated with metabolic dysfunction and increased risk for diabetes, cardiovascular disease, cancer, and early mortality ( 1, 2 ). In both lean and obese states, triacylglycerol is predominately stored within lipid droplets of adipocytes. Perilipin A (PeriA) is the most abundant phosphoprotein on adipocyte lipid droplets and is an important regulator of lipid storage and release (lipolysis) ( 3, 4 ). In the absence of hormonal stimulation (basal state), PeriA functions to inhibit the actions of lipases on stored neutral lipids, thereby maintaining a low rate of constitutive lipolysis (promotes lipid storage) ( 5-10 ). Catecholamines enhance adipocyte lipolysis by stimulating adenylate cyclase activity and consequently activating cAMP-dependent protein kinase A (PKA), which simultaneously phosphorylates perilipin and hormone-sensitive lipase (HSL) ( 3,11,12 ). PKA-dependent phosphorylation of multiple serine residues on perilipin releases CGI-58 from the lipid droplet protein, resulting in enhanced activity of adipose triglyceride lipase (ATGL) ( 13, 14 ) and enhanced HSL accessibility to lipid stores ( 4,5,10,(15)(16)(17). As a result of these combined actions, lipolysis is dramatically increased.Abstract Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specifi c aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholaminestimulated lipolysis was decreased and glucose tolerance signifi cantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our fi ndings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications. -Miyoshi,

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Effects of Perilipin (PLIN) Gene Variation on Metabolic Syndrome Risk and Weight Loss in Obese Children and Adolescents

Abstract: The minor A allele at PLIN4 was associated with higher risk of MS at baseline, whereas the PLIN6 SNP was associated with better weight loss, suggesting that these polymorphisms may predict outcome strategies based on multidisciplinary treatment for OCA.

Cited by 41 publications

References 29 publications

The role of lipid droplets in metabolic disease in rodents and humans

The role of lipid droplets in metabolic disease in rodents and humans

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

Perilipin overexpression in mice protects against diet-induced obesity

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