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Edward M Rubin

Publications and source records attributed to Edward M Rubin.

60 records · Page 4Linked to original sources
PubMed2002

Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.

Since triglycerides (TG) are a major independent risk factor for coronary heart disease, understanding their genetic and environmental determinants is of major importance. Mouse models indicate an inverse relationship between levels of the newly identified apolipoprotein AV (APOAV) and TG concentrations. We have examined the relative influence of human APOA5 variants on plasma lipids, compared to the impact of variation in APOC3 and APOA4 which lie in the same cluster. Single nucleotide polymorphisms (SNPs) in APOA5 (S19W, -1131T>C) and APOA4 (T347S, Q360H) and an APOA4/A5 intergenic T>C SNP were examined in a large study of healthy middle-aged men (n=2808). APOA5 19WW and -1131CC men had 52% and 40% higher TG (P<0.003) compared to common allele homozygotes, respectively, effects which were independent and additive. APOA4 347SS men had 23% lower TG compared to TT men (P<0.002). Haplotype analysis was carried out to identify TG-raising alleles and included, in addition, four previously genotyped APOC3 SNPs (-2845T>G, -482C>T, 1100C>T, and 3238C>G). The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T. This suggests that the TG-lowering effect of APOA4 S347 might merely reflect the strong negative linkage disequilibrium with the common alleles of these variants. Thus variation in APOA5 is associated with differences in TGs in healthy men, independent of those previously reported for APOC3, while association between APOA4 and TG reflects linkage disequilibrium with these sites. The molecular mechanisms for these effects remain to be determined.

Apolipoprotein A-V↗
PubMed2002

Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition.

Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb-/- mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb-/- mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb-/- mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb-/- and wildtype cells was similar, Tnxb-/- fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.

Animals↗
PubMed2002

Paraoxonase 1 overexpression in mice and its effect on high-density lipoproteins.

Paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme believed to protect against the early events of atherogenesis by its ability to hydrolyze oxidized phospholipids. A transgenic mouse overexpressing PON1 (mPON1) was developed to address the question of whether overexpression of PON1 is important in protecting HDL function during oxidative stress. Transgenic mice were obtained that have up to a 5-fold increase in mPON1 activity measured as arylesterase activity [52.7 +/- 17.3 U/ml versus 251.7 +/- 25.1 U/ml for wild-type (WT) and mPON1 high expressers, respectively]; this increase in mPON1 activity was reflected by a 5.3-fold increase in relative mass of the enzyme. Excess mPON1 was associated solely with HDL but did not alter HDL composition, size, or charge. Lecithin:cholesterol acyltransferase (LCAT) on HDL is a sensitive indicator of oxidative stress; exposure of plasmas from both WT and mPON1 overexpresser mice to 0.4 mM copper ions for 2 h showed a 30-40% protection of LCAT activity in mPON1 overexpressers compared to WT. Excess mPON1 also inhibited lipid hydroperoxide formation on HDL. These data strongly suggest that overexpression of mPON1 protects HDL integrity and function.

Animals↗
PubMed2002

Expression profiling and comparative sequence derived insights into lipid metabolism.

Expression profiling and genomic DNA sequence comparisons are increasingly being applied to the identification and analysis of the genes that are involved in lipid metabolism. Not only has genome-wide expression profiling aided in the identification of novel genes that are involved in important processes in lipid metabolism such as sterol efflux, but also the utilization of information from these studies has added to our understanding of the regulation of pathways that participate in the process. Coupled with these gene expression studies, cross-species comparison (a technique used to search for sequences that are conserved through evolution) has proven to be a powerful tool to identify important noncoding regulatory sequences and novel genes that are relevant to lipid biology. An example of the value of this approach was the recent chance discovery of a new apolipoprotein gene (that which encodes apolipoprotein AV) that has dramatic effects on triglyceride metabolism in mice and humans.

Animals↗
PubMed2002

rVista for comparative sequence-based discovery of functional transcription factor binding sites.

Identifying transcriptional regulatory elements represents a significant challenge in annotating the genomes of higher vertebrates. We have developed a computational tool, rVista, for high-throughput discovery of cis-regulatory elements that combines clustering of predicted transcription factor binding sites (TFBSs) and the analysis of interspecies sequence conservation to maximize the identification of functional sites. To assess the ability of rVista to discover true positive TFBSs while minimizing the prediction of false positives, we analyzed the distribution of several TFBSs across 1 Mb of the well-annotated cytokine gene cluster (Hs5q31; Mm11). Because a large number of AP-1, NFAT, and GATA-3 sites have been experimentally identified in this interval, we focused our analysis on the distribution of all binding sites specific for these transcription factors. The exploitation of the orthologous human-mouse dataset resulted in the elimination of > 95% of the approximately 58,000 binding sites predicted on analysis of the human sequence alone, whereas it identified 88% of the experimentally verified binding sites in this region.

Animals↗