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Biomedical subjects

Liam R Brunham

Publications and source records attributed to Liam R Brunham.

12 recordsLinked to original sources
PubMed2026

Predictors of aortic stenosis in homozygous familial hypercholesterolemia: A study from the Canadian HoFH registry.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. This disease is associated with a major risk of both atherosclerotic cardiovascular disease and aortic stenosis (AS). The predictors of AS in this population are not well established. OBJECTIVE: To investigate the univariable and multivariable predictors of AS in patients from the Canadian HoFH registry. METHODS: Individuals from the Canadian HoFH registry were included in this retrospective longitudinal study. Clinical data were obtained from the treating physicians using a standardized questionnaire. Cox proportional hazards models were used to investigate the predictors of AS. The observed lifetime risk of AS was calculated using Kaplan-Meier estimates. RESULTS: Among the 67 patients with HoFH, 25 (37%) developed AS. The mean age at baseline was 22 ± 17 years and women represented 57% of the cohort. The independent predictors of AS were the baseline LDL-C (hazard ratio [HR] 1.22 [1.09-1.35], P = .0003) as well as the presence of at least 1 null genetic variant (HR 3.73 [1.41-9.86], P = .008). Having a baseline LDL-C value above 13 mmol/L was associated with an observed lifelong risk of developing AS approaching 100% within this cohort, whereas having a value below this threshold was associated with a risk of 27% (P = .0002). CONCLUSION: This is the first systematic evaluation within a national HoFH registry to report the univariable and multivariable predictors of AS in patients with HoFH. An external validation of our results in an international cohort of HoFH is warranted.

Aortic stenosis↗
PubMed2006

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

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.

ATP Binding Cassette Transporter 1↗
PubMed2006

Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo.

BACKGROUND: Extrahepatic tissues have long been considered critical contributors of cholesterol to nascent HDL particles in the reverse cholesterol transport pathway, in which ABCA1 plays the crucial role. Recent studies, however, including both overexpression and deletion of ABCA1 selectively in the liver, have highlighted the primary role of the liver in the maintenance of HDL levels in vivo. METHODS AND RESULTS: The availability of mice with complete deletion of ABCA1 (total knockout [TKO]) and with liver-specific deletion of ABCA1 (LSKO) has enabled us to dissect the discrete roles of hepatic relative to extrahepatic ABCA1 in HDL biogenesis. Delivery of adenoviral ABCA1 resulted in selective expression of physiological levels of ABCA1 in the livers of both LSKO and TKO mice, resulting in increased HDL cholesterol (HDL-C). Expression of ABCA1 in the liver of LSKO mice resulted in plasma HDL-C levels that were similar to those in wild-type mice and significantly above those seen in similarly treated TKO mice. HDL particles from ABCA1-expressing LSKO mice were larger and contained significantly increased cholesterol compared with TKO mice. Infusion of human apolipoprotein A-I/phospholipid reconstituted HDL particles normalized plasma HDL-C levels in LSKO mice but had no effect on HDL-C levels in TKO mice. CONCLUSIONS: Although hepatic ABCA1 appears crucial for phospholipid transport, extrahepatic tissues play an important role in cholesterol transfer to nascent HDL particles. These data highlight the discrete and specific roles of both liver and extrahepatic ABCA1 in HDL biogenesis in vivo and indicate that ABCA1 shows lipid cargo selectivity depending on its site of expression.

ATP Binding Cassette Transporter 1↗
PubMed2006

Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro.

Mutations in ATP-binding cassette transporter A1 (ABCA1) cause Tangier disease and familial hypoalphalipoproteinemia, resulting in low to absent plasma high-density lipoprotein cholesterol levels. However, wide variations in clinical lipid phenotypes are observed in patients with mutations in ABCA1. We hypothesized that the various lipid phenotypes would be the direct result of discrete and differing effects of the mutations on ABCA1 function. To determine whether there is a correlation between the mutations and the resulting phenotypes, we generated in vitro 15 missense mutations that have been described in patients with Tangier disease and familial hypoalphalipoproteinemia. Using localization of ABCA1, its ability to induce cell surface binding of apolipoprotein A-I, and its ability to elicit efflux of cholesterol and phospholipids to apolipoprotein A-I we determined that the phenotypes of patients correlate with the severity and nature of defects in ABCA1 function.

Apolipoprotein A-I↗
PubMed2006

Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.

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.

ATP Binding Cassette Transporter 1↗
PubMed2006

Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.

Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.

ATP Binding Cassette Transporter 1↗
PubMed2005

Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.

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.

ATP Binding Cassette Transporter 1↗
PubMed2005

Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.

Patients with Tangier disease exhibit extremely low plasma HDL concentrations resulting from mutations in the ATP-binding cassette, sub-family A, member 1 (ABCA1) protein. ABCA1 controls the rate-limiting step in HDL particle assembly by mediating efflux of cholesterol and phospholipid from cells to lipid-free apoA-I, which forms nascent HDL particles. ABCA1 is widely expressed; however, the specific tissues involved in HDL biogenesis are unknown. To determine the role of the liver in HDL biogenesis, we generated mice with targeted deletion of the second nucleotide-binding domain of Abca1 in liver only (Abca1(-L/-L)). Abca1(-L/-L) mice had total plasma and HDL cholesterol concentrations that were 19% and 17% those of wild-type littermates, respectively. In vivo catabolism of HDL apoA-I from wild-type mice or human lipid-free apoA-I was 2-fold higher in Abca1(-L/-L) mice compared with controls due to a 2-fold increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism. We conclude that in chow-fed mice, the liver is the single most important source of plasma HDL. Furthermore, hepatic, but not extrahepatic, Abca1 is critical in maintaining the circulation of mature HDL particles by direct lipidation of hepatic lipid-poor apoA-I, slowing its catabolism by the kidney and prolonging its plasma residence time.

ATP Binding Cassette Transporter 1↗
PubMed2004

A case of Tangier disease with a novel mutation in the C-terminal region of ATP-binding cassette transporter A1.

Tangier disease (TD), a rare disorder characterized by extremely low levels of high density lipoprotein cholesterol (HDL-C), is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene. Here, we describe a new patient with TD. The 42-year-old proband had obvious juvenile cataracts, mild hepatosplenomegaly, and an extremely low level of HDL-C (1 mg/dl), consistent with the diagnosis of TD. The proband was homozygous for a novel CTC6914-6TT --> 2203X mutation in the carboxy terminus of the ABCA1 protein. ApoAI-mediated cholesterol efflux from patient fibroblasts was markedly decreased compared to control, despite normal levels of protein expression. This indicates that this mutant protein is normally transcribed and exists as a stable product, yet is functionally defective. These results point to a critical role for the intracellular C-terminal region of the ABCA1 gene product in regulating cholesterol efflux and HDL-cholesterol levels.

ATP Binding Cassette Transporter 1↗
PubMed2003

Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene.

Approximately 50 mutations and many single nucleotide polymorphisms have been described in the ABCA1 gene, with mutations leading to Tangier disease and familial hypoalphalipoproteinemia. Homozygotes and heterozygotes for mutations in ABCA1 display a wide range of phenotypes. Identification of ABCA1 as the molecular defect in these diseases has allowed for ascertainment based on genetic status and determination of genotype-phenotype correlations and has permitted us to identify mutations conferring a range of severity of cellular, biochemical, and clinical phenotypes. In this study we review how genetic variation at the ABCA1 locus affects its role in the maintenance of lipid homeostasis and the natural progression of atherosclerosis.

ATP Binding Cassette Transporter 1↗
PubMed2003

Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1.

ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 x 108 to 1.5 x 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 x 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels.

ATP Binding Cassette Transporter 1↗