Human Resistin Stimulates Hepatic Overproduction of Atherogenic ApoB-Containing Lipoprotein Particles by Enhancing ApoB Stability and Impairing Intracellular Insulin Signaling

Costandi, Justina; Melone, M.; Na, Xiaona; Rashid, Shahidur

doi:10.1161/circresaha.110.238949

Cited by 58 publications

(56 citation statements)

References 56 publications

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“…The study by Hivert et al [23] analyzing the association of the rs10401670SNP with diabetes-related traits in the Framingham Offspring Study did not include the relationship of the polymorphism with lipid variables in its analysis. It has been reported that resistin has a direct impact on human hepatic lipid and lipoprotein regulation, stimulating hepatic overproduction of atherogenic ApoBcontaining lipoprotein particles by enhancing Apo B stability [38]. To our knowledge, this is the only study describing the association of a SNP in the resistin gene with resistin and lipid levels in children.…”

Section: Discussionmentioning

confidence: 86%

Association of resistin polymorphisms with resistin levels and lipid profile in children

et al. 2014

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Previous research has found a correlation between resistin and lipid level variations. Polymorphisms in the resistin gene (RETN) could be involved in this relationship, but the results of the different studies are contradictory. The aim of this study was to examine the association between resistin and lipid levels, and to determine whether resistin polymorphisms are associated with resistin levels and lipid profile in prepubertal children and adolescents. The single nucleotide polymorphisms (SNPs) rs1862513 and rs10401670 were analyzed in 442 randomly selected 6- to 8-year-old children and 827 children aged 12-16 years. Anthropometric data were recorded. Lipid profile was determined using standard methods. Serum resistin levels were measured using a multiplexed bead immunoassay. Resistin polymorphisms were determined by TaqMan(®) allelic discrimination assays. A relationship was found between serum levels of resistin and the SNP rs10401670 in 6- to 8-year-old boys. SNP rs10401670 was also related to TC and LDL-cholesterol in 12- to 16-year-old boys and to HDL-C in 12- to 16-year-old girls. SNP rs1862513 was not related to any of the studied variables. Serum resistin levels were significantly and negatively associated with ApoAI levels in 12- to 16-year-old girls. A SNP in the 3'UTR region of RETN (rs10401670) is associated with resistin levels and lipid profile in children, showing different associations depending on age and gender.

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Section: Discussionmentioning

confidence: 86%

Association of resistin polymorphisms with resistin levels and lipid profile in children

et al. 2014

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“…It is possible that the reduction in APOB secretion in the whole-body knockout mouse could be related to sortilin deficiency in extrahepatic tissues. Indeed, sortilin is strongly expressed in brain, adipose, and skeletal muscle, all tissues have that been shown to influence hepatic VLDL production (36,37). It is possible that selective sortilin deficiency in liver only would have a different phenotype related to APOB secretion.…”

Section: Figurementioning

confidence: 99%

Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism

Strong¹,

Ding²,

Edmondson³

et al. 2012

J. Clin. Invest.

199

233

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Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.

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“…Resistin has also been shown to enhance VLDL production by increasing apoB mRNA abundance and stimulating expression of MTP and DNL while reducing insulin signaling pathways. 93 If apoB mRNA were increased by inflammatory cytokines there would be additional apoB for VLDL assembly and secretion, which would contribute to VLDL hypersecretion.…”

Section: Hepatic Inflammation and Inflammatory Cytokines And Vldl Hypmentioning

confidence: 99%

Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Sparks

Adeli

2012

ATVB

192

125

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A central feature of metabolic syndrome is hepatic hypersecretion of very low-density lipoprotein (VLDL), which results in hypertriglyceridemia (HTG), a consistent finding associated with obesity and type 2 diabetes mellitus. Under physiological conditions, insulin signaling regulates VLDL production by targeting apolipoprotein (apo) B for degradation and limiting apoB synthesis.1 Pancreatic release of insulin into the portal vein after eating reduces VLDL output during the postprandial period allowing for transient triglyceride (TG) storage for future secretion. This is consistent with insulin acting as an anabolic hormone stimulating energy storage in both liver and fat. Because of reduced hepatic secretion of VLDL, there is less competition for lipolysis with intestinal lipoproteins resulting in their preferential clearance. Loss of this acute pathway may be the earliest consequence of overnutrition and with it is the loss of the cyclical nature of VLDL production during the postprandial transition. There is then continuous secretion of VLDL and packaging of excess TG into larger sized (VLDL1) and more numerous VLDL particles, inducing HTG. Insulin induction of de novo lipogenesis (DNL) favors TG synthesis and occurs independent of effects on apoB. With insulin resistance, more apoB is available and along with stimulation of DNL, there is hypersecretion of VLDL1. In classical forms of insulin resistance, transcriptional effects increase VLDL production and occur with enhanced gluconeogenesis and forkhead box O1 (FoxO1) activity.2-4 Sustained nuclear localization of FoxO1 increases expression of microsomal triglyceride transfer protein (MTP) 4 and apolipoprotein C-III (apoC-III) 5 resulting in substantial increases in VLDL production above and beyond loss of acute VLDL regulation.2 This review summarizes current understanding of insulin action and insulin resistance related to the complex relationships of apoB and TG in formation of VLDL. This article accompanies the ATVB in Focus: New Developments in Hepatic LipoproteinProduction and Clinical Relevance series that was published in the May 2012 issue. VLDL Assembly and Hepatic VLDL OverproductionVLDL assembly is initiated by the synthesis of B100 (Figure 1), a 550 kDa protein or its shorter form, B48, the protein product of edited apoB mRNA. Editing is a process that introduces a stop codon in the apoB transcript, and in humans this occurs in the intestine. In other species, including mouse and rat, liver makes Abstract-Insulin plays a central role in regulating energy metabolism, including hepatic transport of very low-density lipoprotein (VLDL)-associated triglyceride. Hepatic hypersecretion of VLDL and consequent hypertriglyceridemia leads to lower circulating high-density lipoprotein levels and generation of small dense low-density lipoproteins characteristic of the dyslipidemia commonly observed in metabolic syndrome and type 2 diabetes mellitus. Physiological fluctuations of insulin modulate VLDL secretion, and insulin inhibition of VLDL secretion upon...

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Human Resistin Stimulates Hepatic Overproduction of Atherogenic ApoB-Containing Lipoprotein Particles by Enhancing ApoB Stability and Impairing Intracellular Insulin Signaling

Cited by 58 publications

References 56 publications

Association of resistin polymorphisms with resistin levels and lipid profile in children

Association of resistin polymorphisms with resistin levels and lipid profile in children

Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism

Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

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