Metabolism and Genetics of Hypobetalipoproteinemia
Ontology highlight
ABSTRACT: Hypobetalipoproteinemia is characterized by extremely low levels of low-density lipoprotein cholesterol. Familial hypobetalipoproteinemia (FHBL) is a monogenic form of hypobetalipoproteinemia caused by mutations in the APOB gene. There are cases of hypobetalipoproteinemia not caused by mutations in APOB, however. The purpose of this study is to identify novel genetic causes of hypobetalipoproteinemia.
PROVIDER: phs000561.v1.p1 | EGA |
REPOSITORIES: EGA
Publications
Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.
Musunuru Kiran K Pirruccello James P JP Do Ron R Peloso Gina M GM Guiducci Candace C Sougnez Carrie C Garimella Kiran V KV Fisher Sheila S Abreu Justin J Barry Andrew J AJ Fennell Tim T Banks Eric E Ambrogio Lauren L Cibulskis Kristian K Kernytsky Andrew A Gonzalez Elena E Rudzicz Nicholas N Engert James C JC DePristo Mark A MA Daly Mark J MJ Cohen Jonathan C JC Hobbs Helen H HH Altshuler David D Schonfeld Gustav G Gabriel Stacey B SB Yue Pin P Kathiresan Sekar S
The New England journal of medicine 20101013 23
We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby incr ...[more]
Similar Datasets
Project description:<p>Hypobetalipoproteinemia is characterized by extremely low levels of low-density lipoprotein cholesterol. Familial hypobetalipoproteinemia (FHBL) is a monogenic form of hypobetalipoproteinemia caused by mutations in the APOB gene. There are cases of hypobetalipoproteinemia not caused by mutations in APOB, however. The purpose of this study is to identify novel genetic causes of hypobetalipoproteinemia.</p>
| phs000561 | dbGaP
Project description:Emerging in vivo and vitro data suggest that white tea extract (WTE) is capable of favourably modulating metabolic syndrome, especially by ameliorating abnormal lipid metabolism. Microarray-based gene expression profiling was performed in HepG2 cells to analyze the effects of WTE from a systematic perspective. Gene Ontology and pathway analysis revealed that WTE significantly affected pathways related to lipid metabolism. WTE significantly downregulated apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression and thereby reduced the production of very-low-density lipoprotein. In the meanwhile, WTE stimulated low-density lipoprotein-cholesterol (LDL-c) uptake through targeting low-density lipoprotein receptor (LDLR), as a consequence of the activation of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator-activated receptor δ (PPARδ). Furthermore, WTE significantly downregulated triglycerides synthetic genes and reduced intracellular triglycerides accumulation. Besides, we demonstrated that the tea catechins epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) are abundant in WTE and contribute to the regulation of cholesterol metabolism related genes, including LDLR, MTTP and APOB. Our findings suggest white tea plays important roles in ameliorating abnormal lipid metabolism in vitro.
2018-12-07 | GSE123402 | GEO
Project description:<p>The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.</p> <p>In this study, we seek to identify the genetic cause of two monogenic lipid disorders-severe hypercholesterolemia and familial hypoalphalipoproteinemia. Monogenic severe hypercholesterolemia is clinically characterized by elevated total and low-density lipoprotein (LDL) cholesterol levels in plasma. Elevated LDL-cholesterol levels lead to excessive deposition of cholesterol in arterial walls, which eventually results in accelerated atherosclerosis and premature cardiovascular disease (CVD). Monogenic hypercholesterolemia has a prevalence of approximately one in 500 individuals, making it one of the most common inherited disorders. To date, mutations in the LDL receptor (LDLR) ligand-binding domains of APOB and PCSK9 have been shown to cause hypercholesterolemia. While mutations in these genes can explain a large percentage of clinically diagnosed patients, the underlying molecular determinant in a substantial fraction of patients remains unknown.</p> <p>Familial hypoalphalipoproteinemia (low HDL-C) is defined by an HDL-C below the age- and sex- specific 10th percentile. ABCA1, LCAT, and APOA1 are known to cause familial hypoalphalipoproteinemia. We hypothesize that: (1) additional novel genes responsible for Mendelian forms of low HDL-C exist; and (2) the causal gene and mutation(s) in each family may be discovered with exome analysis of just a few affected individuals in each pedigree.</p>
| phs000587 | dbGaP
Project description:Increased serum apoB and associated low density lipoprotein cholesterol (LDL) levels are well correlated with an increased risk of coronary disease. Apo E-/- and LDLr -/- mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr+/- CETP+/- hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel siRNAs formulated in lipid nanoparticles (LNPs). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr+/- CETP+/- mice. ApoB targeting is specific, dose dependent and shows lipid lowering effects for over three weeks. Although specific TGs were affected by ApoB KD, and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality. Two oligoes specific for ApoB were used to knock down apoB expression in C57Bl6 or B6-Ldlr(tm1)Tg(APOA1-CETP) mice. Gene expression profiling was performed with Affymetrix Merck Custom Mouse 1.0 microarrays (GPL9734).
2010-11-22 | E-GEOD-23088 | biostudies-arrayexpress
Project description:Increased serum apoB and associated low density lipoprotein cholesterol (LDL) levels are well correlated with an increased risk of coronary disease. Apo E-/- and LDLr -/- mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr+/- CETP+/- hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel siRNAs formulated in lipid nanoparticles (LNPs). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr+/- CETP+/- mice. ApoB targeting is specific, dose dependent and shows lipid lowering effects for over three weeks. Although specific TGs were affected by ApoB KD, and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.
2010-11-22 | GSE23088 | GEO
Project description:We report the transcriptome of atherosclerosis-specific murine CD4+ T cells in atherosclerosis that recognize a peptide from ApoB-100, the core protein of low-density lipoprotein (LDL). Our data reveal a unique transcriptome of ApoB-specific T cells that is similar to T-regulatory T cells and changes during disease progression in a pathogenic T-helper type -1 and -17 like transcriptome.
2020-05-21 | GSE149067 | GEO
Project description:The hypocholesterolemic effect of probiotics has been observed, but the molecular mechanism of probiotic-host interaction is still obscure. In this study, DNA microarray technology was used to explore the gene expression profile of liver of hypercholesterolemic rats caused by administration of probiotic Lactobacillus casei Zhang, which can decrease the serum triglyceride, low-density lipoprotein cholesterol, hepatic cholesterol and triglyceride of hypercholesterolemic rats.
2011-12-31 | GSE23740 | GEO
Project description:We report the single cell transcriptome of atherosclerosis-specific murine CD4+ T cells that recognize a peptide from ApoB-100, the core protein of low-density lipoprotein (LDL). Our data reveal a unique single cell transcriptome of ApoB-specific T cells that is similar to T-regulatory T but shows an overlap with the transcriptome of pathogenic T-helper type -1 and -17 cells on a single cell level.
2020-05-21 | GSE149068 | GEO
Project description:Morgan2016 - Dynamics of cholesterol
metabolism and ageing
This model is described in the article:
Mathematically modelling the
dynamics of cholesterol metabolism and ageing.
Morgan AE, Mooney KM, Wilkinson SJ,
Pickles NA, Mc Auley MT.
BioSystems 2016 Jul; 145: 19-32
Abstract:
Cardiovascular disease (CVD) is the leading cause of
morbidity and mortality in the UK. This condition becomes
increasingly prevalent during ageing; 34.1% and 29.8% of males
and females respectively, over 75 years of age have an
underlying cardiovascular problem. The dysregulation of
cholesterol metabolism is inextricably correlated with
cardiovascular health and for this reason low density
lipoprotein cholesterol (LDL-C) and high density lipoprotein
cholesterol (HDL-C) are routinely used as biomarkers of CVD
risk. The aim of this work was to use mathematical modelling to
explore how cholesterol metabolism is affected by the ageing
process. To do this we updated a previously published
whole-body mathematical model of cholesterol metabolism to
include an additional 96 mechanisms that are fundamental to
this biological system. Additional mechanisms were added to
cholesterol absorption, cholesterol synthesis, reverse
cholesterol transport (RCT), bile acid synthesis, and their
enterohepatic circulation. The sensitivity of the model was
explored by the use of both local and global parameter scans.
In addition, acute cholesterol feeding was used to explore the
effectiveness of the regulatory mechanisms which are
responsible for maintaining whole-body cholesterol balance. It
was found that our model behaves as a hypo-responder to
cholesterol feeding, while both the hepatic and intestinal
pools of cholesterol increased significantly. The model was
also used to explore the effects of ageing in tandem with three
different cholesterol ester transfer protein (CETP) genotypes.
Ageing in the presence of an atheroprotective CETP genotype,
conferring low CETP activity, resulted in a 0.6% increase in
LDL-C. In comparison, ageing with a genotype reflective of high
CETP activity, resulted in a 1.6% increase in LDL-C. Thus, the
model has illustrated the importance of CETP genotypes such as
I405V, and their potential role in healthy ageing.
This model is hosted on
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MODEL1508170000.
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2017-06-01 | MODEL1508170000 | BioModels
Project description:Atherosclerosis is characterized by thickening of the arterial wall and is the primary cause of the coronary artery disease and cerebrovascular disease, two of the most common causes of illness and death worldwide. One of the leading risk factors for development of atherosclerosis is familial hypercholesterolemia. Familial hypercholesterolemia is an autosomal dominant disorder, which is caused by mutations mainly located in the low-density lipoprotein receptor (LDLR) gene. It is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. Aim of this study was to find atherosclerotic markers in white blood cells of patients compared to healthy controls. None of these patients exhibited symptoms of atherosclerosis by standard diagnostic methods; however, transcriptome analysis of blood RNA indicated changes in ubiquitin proteolysis and cell adhesion system as expected in initiation steps of atherosclerosis.
2008-12-18 | GSE13985 | GEO