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Artikel ; Online: Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels.

Brunham, Liam R / Kruit, Janine K / Pape, Terry D / Parks, John S / Kuipers, Folkert / Hayden, Michael R

2006 Band 99, Heft 7, Seite(n) 672–674

Abstract: ABCA1 controls the rate-limiting step in HDL particle formation and is therefore an attractive molecular target for raising HDL levels and protecting against atherosclerosis. Intestinal ABCA1 significantly and independently contributes to plasma HDL ... ...

Abstract	ABCA1 controls the rate-limiting step in HDL particle formation and is therefore an attractive molecular target for raising HDL levels and protecting against atherosclerosis. Intestinal ABCA1 significantly and independently contributes to plasma HDL cholesterol levels in mice, suggesting that induction of intestinal ABCA1 expression may raise plasma HDL cholesterol levels. We evaluated the ability of a synthetic Liver X Receptor (LXR) agonist, GW3965, to raise plasma HDL cholesterol levels in control mice and mice with liver- or intestinal-specific deletion of the Abca1 gene. Oral treatment with GW3965 increased the expression of ABCA1 by approximately 6-fold (P=0.004) as well as other LXR target genes in the intestines of mice, with no change in the hepatic expression of these genes. This resulted in a significant approximately 48% elevation of plasma HDL cholesterol levels in wild-type mice (P<0.01) with no change in plasma triglycerides. A similar increase in HDL cholesterol was observed in mice lacking hepatic ABCA1, indicating that the increase in plasma HDL cholesterol was independent of hepatic ABCA1. This effect was completely abrogated in mice lacking intestinal ABCA1. These data indicate that intestinal ABCA1 may be an attractive therapeutic target for raising HDL levels while avoiding the hepatic lipogenesis and hypertriglyceridemia typical of systemic LXR activation.
Mesh-Begriff(e)	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/biosynthesis ; ATP-Binding Cassette Transporters/genetics ; Animals ; Benzoates/pharmacology ; Benzylamines/pharmacology ; Cholesterol, HDL/blood ; DNA-Binding Proteins/agonists ; Intestines/metabolism ; Liver/metabolism ; Liver X Receptors ; Mice ; Mice, Knockout/genetics ; Orphan Nuclear Receptors ; Receptors, Cytoplasmic and Nuclear/agonists
Chemische Substanzen	ATP Binding Cassette Transporter 1 ; Benzoates ; Benzylamines ; Cholesterol, HDL ; DNA-Binding Proteins ; GW 3965 ; Liver X Receptors ; Orphan Nuclear Receptors ; Receptors, Cytoplasmic and Nuclear
Sprache	Englisch
Erscheinungsdatum	2006-09-29
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/01.RES.0000244014.19589.8e
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.

Brunham, Liam R / Singaraja, Roshni R / Pape, Terry D / Kejariwal, Anish / Thomas, Paul D / Hayden, Michael R

PLoS genetics

2005 Band 1, Heft 6, Seite(n) e83

Abstract: The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to ... ...

Abstract	The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation.
Mesh-Begriff(e)	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/genetics ; Amino Acid Substitution ; Cell Line ; Cholesterol/metabolism ; Conserved Sequence ; DNA, Complementary/genetics ; Evolution, Molecular ; Genetic Variation ; Genome, Human ; Humans ; Mutation, Missense ; Phenotype ; Polymorphism, Single Nucleotide ; Reverse Transcriptase Polymerase Chain Reaction
Chemische Substanzen	ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; DNA, Complementary ; Cholesterol (97C5T2UQ7J)
Sprache	Englisch
Erscheinungsdatum	2005-12
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.0010083
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.

Brunham, Liam R / Kruit, Janine K / Pape, Terry D / Timmins, Jenelle M / Reuwer, Anne Q / Vasanji, Zainisha / Marsh, Brad J / Rodrigues, Brian / Johnson, James D / Parks, John S / Verchere, C Bruce / Hayden, Michael R

Nature medicine

2007 Band 13, Heft 3, Seite(n) 340–347

Abstract: Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within ... ...

Abstract	Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.
Mesh-Begriff(e)	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/biosynthesis ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/physiology ; Animals ; Cholesterol/metabolism ; Glucose/metabolism ; Homeostasis/drug effects ; Homeostasis/physiology ; Hypoglycemic Agents/pharmacology ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Thiazolidinediones/pharmacology
Chemische Substanzen	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Hypoglycemic Agents ; Insulin ; Thiazolidinediones ; Cholesterol (97C5T2UQ7J) ; 2,4-thiazolidinedione (AA68LXK93C) ; Glucose (IY9XDZ35W2)
Sprache	Englisch
Erscheinungsdatum	2007-02-18
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm1546
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.

Brunham, Liam R / Kruit, Janine K / Iqbal, Jahangir / Fievet, Catherine / Timmins, Jenelle M / Pape, Terry D / Coburn, Bryan A / Bissada, Nagat / Staels, Bart / Groen, Albert K / Hussain, M Mahmood / Parks, John S / Kuipers, Folkert / Hayden, Michael R

The Journal of clinical investigation

2006 Band 116, Heft 4, Seite(n) 1052–1062

Abstract: Plasma HDL cholesterol levels are inversely related to risk for atherosclerosis. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation, the assembly of free cholesterol and phospholipids with ...

Abstract	Plasma HDL cholesterol levels are inversely related to risk for atherosclerosis. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation, the assembly of free cholesterol and phospholipids with apoA-I. ABCA1 is expressed in many tissues; however, the physiological functions of ABCA1 in specific tissues and organs are still elusive. The liver is known to be the major source of plasma HDL, but it is likely that there are other important sites of HDL biogenesis. To assess the contribution of intestinal ABCA1 to plasma HDL levels in vivo, we generated mice that specifically lack ABCA1 in the intestine. Our results indicate that approximately 30% of the steady-state plasma HDL pool is contributed by intestinal ABCA1 in mice. In addition, our data suggest that HDL derived from intestinal ABCA1 is secreted directly into the circulation and that HDL in lymph is predominantly derived from the plasma compartment. These data establish a critical role for intestinal ABCA1 in plasma HDL biogenesis in vivo.
Mesh-Begriff(e)	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/metabolism ; Animals ; Cholesterol, HDL/blood ; Cholesterol, HDL/metabolism ; Fluorescent Antibody Technique ; Intestinal Mucosa/metabolism ; Intestines/enzymology ; Lymph/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic
Chemische Substanzen	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Cholesterol, HDL
Sprache	Englisch
Erscheinungsdatum	2006-03-16
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI27352
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood.

Devon, Rebecca S / Schwab, Claudia / Topp, Justin D / Orban, Paul C / Yang, Yu-Zhou / Pape, Terry D / Helm, Jeffrey R / Davidson, Tara-Lynne / Rogers, Daniel A / Gros-Louis, Francois / Rouleau, Guy / Horazdovsky, Bruce F / Leavitt, Blair R / Hayden, Michael R

Neurobiology of disease

2004 Band 18, Heft 2, Seite(n) 243–257

Abstract: Mutations in the ALS2 gene, which encodes alsin, cause autosomal recessive juvenile-onset amyotrophic lateral sclerosis (ALS2) and related conditions. Using both a novel monoclonal antibody and LacZ knock-in mice, we demonstrate that alsin is widely ... ...

Abstract	Mutations in the ALS2 gene, which encodes alsin, cause autosomal recessive juvenile-onset amyotrophic lateral sclerosis (ALS2) and related conditions. Using both a novel monoclonal antibody and LacZ knock-in mice, we demonstrate that alsin is widely expressed in neurons of the CNS, including the cortex, brain stem and motor neurons of the spinal cord. Interestingly, the highest levels of alsin are found in the molecular layer of the cerebellum, a brain region not previously implicated in ALS2. During development, alsin is expressed by day E9.5, but CNS expression does not become predominant until early postnatal life. At the subcellular level, alsin is tightly associated with endosomal membranes and is likely to be part of a large protein complex that may include the actin cytoskeleton. ALS2 is present in primates, rodents, fish and flies, but not in the nematode worm or yeast, and is more highly conserved than expected among mammals. Additionally, the product of a second, widely expressed gene, ALS2 C-terminal like (ALS2CL), may subserve or modulate some of the functions of alsin as an activator of Rab and Rho GTPases.
Mesh-Begriff(e)	Actin Cytoskeleton/metabolism ; Adaptor Proteins, Signal Transducing ; Animals ; Anopheles ; Carrier Proteins/genetics ; Central Nervous System/embryology ; Central Nervous System/growth & development ; Central Nervous System/metabolism ; Cerebellar Cortex/embryology ; Cerebellar Cortex/growth & development ; Cerebellar Cortex/metabolism ; Drosophila melanogaster ; Endosomes/metabolism ; Gene Expression Regulation, Developmental/genetics ; Genes, Reporter/genetics ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Lac Operon/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Sequence Data ; Nerve Tissue Proteins/genetics ; Neurons/metabolism ; Pan troglodytes ; Rats ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; Species Specificity ; Takifugu ; Zebrafish ; Zebrafish Proteins/genetics
Chemische Substanzen	ALS2 protein, human ; ALS2CL protein, human ; Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Guanine Nucleotide Exchange Factors ; Nerve Tissue Proteins ; Zebrafish Proteins ; als2a protein, zebrafish
Sprache	Englisch
Erscheinungsdatum	2004-02-18
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2004.10.002
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.

Papanikolaou, George / Samuels, Mark E / Ludwig, Erwin H / MacDonald, Marcia L E / Franchini, Patrick L / Dubé, Marie-Pierre / Andres, Lisa / MacFarlane, Julie / Sakellaropoulos, Nikos / Politou, Marianna / Nemeth, Elizabeta / Thompson, Jay / Risler, Jenni K / Zaborowska, Catherine / Babakaiff, Ryan / Radomski, Christopher C / Pape, Terry D / Davidas, Owen / Christakis, John /

Brissot, Pierre / Lockitch, Gillian / Ganz, Tomas / Hayden, Michael R / Goldberg, Y Paul

Nature genetics

2003 Band 36, Heft 1, Seite(n) 77–82

Abstract: Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to ... ...

Abstract	Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.
Mesh-Begriff(e)	Adolescent ; Adult ; Amino Acid Sequence ; Base Sequence ; Child ; Chromosomes, Human, Pair 1 ; GPI-Linked Proteins ; Hemochromatosis/genetics ; Humans ; Iron Overload ; Membrane Proteins/genetics ; Middle Aged ; Molecular Sequence Data ; Mutation/genetics
Chemische Substanzen	GPI-Linked Proteins ; HJV protein, human ; Membrane Proteins
Sprache	Englisch
Erscheinungsdatum	2003-11-30
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/ng1274
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

Acuña-Alonzo, Víctor / Flores-Dorantes, Teresa / Kruit, Janine K / Villarreal-Molina, Teresa / Arellano-Campos, Olimpia / Hünemeier, Tábita / Moreno-Estrada, Andrés / Ortiz-López, Ma Guadalupe / Villamil-Ramírez, Hugo / León-Mimila, Paola / Villalobos-Comparan, Marisela / Jacobo-Albavera, Leonor / Ramírez-Jiménez, Salvador / Sikora, Martin / Zhang, Lin-Hua / Pape, Terry D / Granados-Silvestre, Ma de Angeles / Montufar-Robles, Isela / Tito-Alvarez, Ana M /

Zurita-Salinas, Camilo / Bustos-Arriaga, José / Cedillo-Barrón, Leticia / Gómez-Trejo, Celta / Barquera-Lozano, Rodrigo / Vieira-Filho, Joao P / Granados, Julio / Romero-Hidalgo, Sandra / Huertas-Vázquez, Adriana / González-Martín, Antonio / Gorostiza, Amaya / Bonatto, Sandro L / Rodríguez-Cruz, Maricela / Wang, Li / Tusié-Luna, Teresa / Aguilar-Salinas, Carlos A / Lisker, Ruben / Moises, Regina S / Menjivar, Marta / Salzano, Francisco M / Knowler, William C / Bortolini, M Cátira / Hayden, Michael R / Baier, Leslie J / Canizales-Quinteros, Samuel

Human molecular genetics

2010 Band 19, Heft 14, Seite(n) 2877–2885

Abstract: It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently ...

Abstract	It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.
Mesh-Begriff(e)	ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/physiology ; Adult ; Alleles ; Cholesterol, HDL/blood ; Cholesterol, HDL/genetics ; Female ; Gene Frequency ; Genetics, Population ; Genome-Wide Association Study ; Geography ; Haplotypes ; Humans ; Indians, North American/genetics ; Linkage Disequilibrium ; Male ; Selection, Genetic
Chemische Substanzen	ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Cholesterol, HDL
Sprache	Englisch
Erscheinungsdatum	2010-04-23
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddq173
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels.

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Artikel ; Online: Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.

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Artikel: Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.

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Artikel: Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.

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Artikel: Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood.

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Artikel: Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.

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Artikel ; Online: A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

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