👤 Akiko Maehara

Despite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive. This study assessed changes in plaque morphology using intravascular imaging, with a comprehensive evaluation of cholesterol efflux capacity (CEC) and peripheral blood mononuclear cell (PBMC) transcriptomics in patients receiving high-dose statin therapy. In a prospective study, 85 patients with stable coronary artery disease underwent percutaneous coronary intervention for a culprit lesion, followed by intracoronary multimodality imaging, including optical coherence tomography (OCT) of an obstructive nonculprit lesion. All subjects received 40 mg of rosuvastatin daily for 8 to 12 weeks, when the nonculprit lesion was reimaged and intervention performed. Blood samples were drawn at both times to assess CEC and transcriptomic profile in PBMC. Baseline OCT minimal fibrous cap thickness (FCT) was 100.9 ± 41.7 μm, which increased to 108.6 ± 39.6 μm at follow-up, and baseline CEC was 0.81 ± 0.14, which increased at follow-up to 0.84 ± 0.14 (p = 0.003). Thin-cap fibroatheroma prevalence decreased from 20.0% to 7.1% (p = 0.003). Changes in FCT were independently associated with CEC increase by multivariate analysis (β: 0.30; p = 0.01). PBMC microarray analysis detected 117 genes that were differentially expressed at follow-up compared to baseline, including genes playing key roles in cholesterol synthesis (SQLE), regulation of fatty acids unsaturation (FADS1), cellular cholesterol uptake (LDLR), efflux (ABCA1 and ABCG1), and inflammation (DHCR24). Weighted coexpression network analysis revealed unique clusters of genes associated with favorable FCT and CEC changes. The study demonstrated an independent association between fibrous cap thickening and improved CEC that may contribute to morphological changes suggesting plaque stabilization among patients taking intensive statin therapy. Furthermore, the significant perturbations in PBMC transcriptome may help determine the beneficial effects of statin on plaque stabilization. (Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering [YELLOW II]; NCT01837823). Show less

Here, we explored the genetic interactions between diabetes and oncogenic single-nucleotide polymorphisms (SNPs) that determine colorectal cancer (CRC) morbidity. 8q24 rs6983267 polymorphism analysis and cDNA microarray were performed in 107 CRCs to identify the genes associated with diabetes and the oncogenic SNP. Then clinical significance of the gene was validated in 132 CRCs. Meta-analysis of microarray data and diabetic comorbidity was performed. Of genes associated with a minor SNP allele at 8q24, diabetes, and MYC overexpression, apolipoprotein A-IV (ApoA-IV) was associated with oncogenesis and poor prognosis in CRC patients. Patients with high ApoA-IV expression showed significantly poorer prognosis by univariate and multivariate analysis. Meta-analysis revealed lipid metabolism was associated with ApoA-IV-related oncogenesis in diabetic patients. Changes in lipid metabolism associated with aberrant expression of ApoA-IV were risks for CRC oncogenesis. Show less

In interspecific hybrids between Drosophila melanogaster and Drosophila simulans, the D. simulans nucleoporin-encoding Nup96(sim) and Nup160(sim) can cause recessive lethality if the hybrid does not also inherit the D. simulans X chromosome. In addition, Nup160(sim) leads to recessive female sterility in the D. melanogaster genetic background. Here, we conducted carefully controlled crosses to better understandthe relationship between Nup96(sim) and Nup160(sim). Nup96(sim) did not lead to female sterility in the D. melanogaster genetic background, and double introgression of Nup96(sim) and Nup160(sim) did not generally lead to lethality when one was heterozygous and the other homozygous (hemizygous). It appears that introgression of additional autosomal D. simulans genes is necessary to cause lethality and that the effect of the introgression is dominant to D. melanogaster alleles. Interestingly, the genetic background affected dominance of Nup96(sim), and double introgression carrying homozygous Nup96(sim) and hemizygous Nup160(sim) resulted in lethality. Thus, Nup96(sim) and Nup160(sim) seem to be two components of the same incompatibility. Show less

Previous reports have suggested that the Nucleoporin 160 (Nup160) gene of Drosophila simulans (Nup160(sim)) causes the hybrid inviability, female sterility, and morphological anomalies that are observed in crosses with D. melanogaster. Here we have confirmed this observation by transposon excision from the P{EP}Nup160(EP372) insertion mutation of D. melanogaster. Null mutations of the Nup160 gene resulted in the three phenotypes caused by Nup160(sim), but revertants of the gene did not. Interestingly, several mutations produced by excision partially complemented hybrid inviability, female sterility, or morphological anomalies. In the future, these mutations will be useful to further our understanding of the developmental mechanisms of reproductive isolation. Based on our analyses with the Nup160(sim) introgression line, the lethal phase of hybrid inviability was determined to be during the early pupal stage. Our analysis also suggested that homozygous Nup160(sim) in D. melanogaster leads to slow development. Thus, Nup160(sim) is involved in multiple aspects of reproductive isolation between these two species. Show less

We have been analyzing genes for reproductive isolation by replacing Drosophila melanogaster genes with homologs from Drosophila simulans by interspecific backcrossing. Among the introgressions established, we found that a segment of the left arm of chromosome 2, Int(2L)S, carried recessive genes for hybrid sterility and inviability. That nuclear pore protein 160 (Nup160) in the introgression region is involved in hybrid inviability, as suggested by others, was confirmed by the present analysis. Male hybrids carrying an X chromosome of D. melanogaster were not rescued by the Lethal hybrid rescue (Lhr) mutation when the D. simulans Nup160 allele was made homozygous or hemizygous. Furthermore, we uniquely found that Nup160 is also responsible for hybrid sterility. Females were sterile when D. simulans Nup160 was made homozygous or hemizygous in the D. melanogaster genetic background. Genetic analyses indicated that the D. simulans Nup160 introgression into D. melanogaster was sufficient to cause female sterility but that other autosomal genes of D. simulans were also necessary to cause lethality. The involvement of Nup160 in hybrid inviability and female sterility was confirmed by transgene experiment. Show less

We previously studied fatty acid metabolism in the liver of nonalcoholic fatty liver disease (NAFLD) and reported the activation of the LXRalpha-SREBP-1c pathway in hepatocytes. LXRalpha regulates cholesterol metabolism as well as fatty acid metabolism, and its agonistic ligands are oxysterols. Moreover, there is some evidence that excess cholesterol intake is involved in the onset of NAFLD. Therefore, in this study, we examined the expression of cholesterol metabolism-associated genes in the NAFLD liver by real-time PCR. Expression of LXRalpha and ACAT1 was up-regulated in NAFLD and this was more noticeable in non-obese rather than in obese patients. Although the expression of the LDL receptor, which acts on cholesterol uptake, and of SREBP-2, a positive key regulator of cholesterol, was suppressed, the expression of enzymes that promote cholesterol synthesis was uniformly increased in NAFLD. Gene expression of apoB100 and microsomal triglyceride transfer protein, which are associated with VLDL secretion, and ABCG5, which is involved in cholesterol excretion, was significantly elevated in NAFLD. Because cholesterol accumulates in hepatocytes in NAFLD liver, cholesterol uptake and synthesis should be physiologically down-regulated. However, cholesterol synthesis was activated in NAFLD liver, meaning that cholesterol metabolism is dysregulated in NAFLD. Overproduction of cholesterol may lead to an increased level of oxysterols, activation of LXRalpha and SREBP-1c, and enhanced fatty acid synthesis. Show less