EMERGE Genome Wide Association Study of Cataract and Low HDL cholesterol
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PROVIDER: PRJNA75469 | ENA |
REPOSITORIES: ENA
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Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3M-bM-^@M-2 splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism. Mutant mice were generated as part of The Jackson LaboratoryM-bM-^@M-^Ys Heart, Lung, Blood, and Sleep Disorder Mutagenesis Program by treating male C57BL/6J (B6) mice with N-ethyl-N-nitrosourea (ENU). Third generation (G3) mice were phenotyped to ensure capture of both dominant and recessive mutations. Two unique G3 animals with low HDL cholesterol levels were then used to establish new inbred lines (Hlb218 and Hlb320) by mating them with B6 mice and intercrossing the offspring with low HDL cholesterol for 7 generations. Livers from 3 Hlb218, 3 Hlb320 males, and 6 B6 male controls were obtained for gene expression analysis. The samples were randomized over Illumina Mouse-6 Expression 1.1 BeadChips .
2012-06-30 | E-GEOD-37902 | biostudies-arrayexpress
Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3′ splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism.
2012-07-01 | GSE37902 | GEO
Project description:eMERGE Genome Wide Association Study of Cataract and Low HDL cholesterol
| PRJNA75471 | ENA
Project description:Cholesterol is an essential cell membrane component and precursor in metabolic pathways. Control of cholesterol levels is essential to human health. The endocrine hormone FGF19 potently inhibits CYP7A1, which controls a key step in cholesterol catabolism. However, the molecular mechanisms that integrate FGF19 with other cholesterol metabolic pathways are incompletely understood. Here we show that FGF19 and analogue promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling without inducing hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with FGF19 analogue dramatically reduced atherosclerotic lesion area in aortas. In healthy human volunteers, FGF19 analogue caused a placebo-adjusted increase in HDL cholesterol levels of 26% in seven days. These findings outline a regulatory role for FGF19 in cholesterol metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis. We used microarrays to detail the global programme of gene expression affected by FGF19 treatment in mice.
2019-01-25 | GSE117855 | GEO
Project description:Specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis. Carriers do not exhibit increased cardiovascular disease risk despite reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of L75P and L174S patients presents a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.
2020-11-20 | PXD021266 | Pride
Project description:Background: High density lipoprotein (HDL) protects the artery wall by removing cholesterol from lipid-laden macrophages. However, recent evidence suggests that it might also inhibit atherogenesis by combating inflammation. Methods and Results: To identify potential anti-inflammatory mechanisms, we challenged macrophages with lipopolysaccharide (LPS), an inflammatory microbial ligand for Toll-like receptor 4 (TLR4). HDL inhibited the expression of 33% (301 of 911) of the genes normally induced by LPS, microarray analysis revealed. One of its major targets was the type I interferon response pathway, a family of potent viral immunoregulators controlled by TLR4 and the TRAM/TRIF signaling pathway. Unexpectedly, HDL’s ability to inhibit gene expression was independent of cellular cholesterol stores. Moreover, it was unaffected by downregulation of two ATP-binding cassette transporters, ABCA1 and ABCG1, that promote cholesterol efflux. To examine the pathway’s potential in vivo relevance, we used mice deficient in apolipoprotein (apo) A-I, HDL’s major protein. After infection with Salmonella (a Gram-negative bacterium that expresses LPS), apoA-I–deficient mice had 6-fold higher plasma levels of interferon-beta-a key regulator of the type I interferon response than did wild-type mice. Conclusions: HDL inhibits a subset of LPS-stimulated macrophage genes that regulate the type I interferon response, and its action is independent of sterol metabolism. These findings raise the possibility that regulation of macrophage genes by HDL might link innate immunity and cardioprotection. 12 arrays, 3 experimental groups, mMncN (no treatment), mMncL (LPS treated, exposed for 4 h to serum-free medium or serum-free medium supplemented with 100 ng/mL of LPS), and mMwtL (HDL treated, Macrophages were treated for 4 h with serum-free medium or serum-free medium supplemented with 50 mg/mL of HDL, washed twice with PBS).
2010-10-01 | E-GEOD-19340 | biostudies-arrayexpress
Project description:Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL.
2013-12-08 | GSE44034 | GEO
Project description:The Shumiya cataract rat (SCR) is a model for hereditary cataract. Two-third of these rats develop lens opacity within 10-11-weeks. Onset of cataract is attributed to the synergetic effect of lanosterol synthase (Lss) and farnesyl-diphosphate farnesyltransferase 1 (Fdft1) mutant alleles that lead to cholesterol deficiency in the lenses, which in turn adversely affects lens biology including the growth and differentiation of lens epithelial cells (LECs). Nevertheless, the molecular events and changes in gene expression associated with the onset of lens opacity in SCR is poorly understood. Our study aimed to identify the gene expression patterns during cataract formation in SCRs, which may be responsible for cataractogenesis in SCR.
2020-07-31 | GSE152616 | GEO
Project description:High-density lipoproteins (HDL) are nanoparticles with >80 associated proteins, phospholipids, cholesterol and cholesteryl esters. We have identified and quantified the ultracentrifugation isolated HDL proteome across 93 strains of mice, a diverse inbred strains of mice, Hybrid Mouse Diversity Panel (HMDP).
2019-04-24 | PXD009473 | Pride
Project description:Background: High density lipoprotein (HDL) protects the artery wall by removing cholesterol from lipid-laden macrophages. However, recent evidence suggests that it might also inhibit atherogenesis by combating inflammation. Methods and Results: To identify potential anti-inflammatory mechanisms, we challenged macrophages with lipopolysaccharide (LPS), an inflammatory microbial ligand for Toll-like receptor 4 (TLR4). HDL inhibited the expression of 33% (301 of 911) of the genes normally induced by LPS, microarray analysis revealed. One of its major targets was the type I interferon response pathway, a family of potent viral immunoregulators controlled by TLR4 and the TRAM/TRIF signaling pathway. Unexpectedly, HDL’s ability to inhibit gene expression was independent of cellular cholesterol stores. Moreover, it was unaffected by downregulation of two ATP-binding cassette transporters, ABCA1 and ABCG1, that promote cholesterol efflux. To examine the pathway’s potential in vivo relevance, we used mice deficient in apolipoprotein (apo) A-I, HDL’s major protein. After infection with Salmonella (a Gram-negative bacterium that expresses LPS), apoA-I–deficient mice had 6-fold higher plasma levels of interferon-beta-a key regulator of the type I interferon response than did wild-type mice. Conclusions: HDL inhibits a subset of LPS-stimulated macrophage genes that regulate the type I interferon response, and its action is independent of sterol metabolism. These findings raise the possibility that regulation of macrophage genes by HDL might link innate immunity and cardioprotection.
2010-10-01 | GSE19340 | GEO