Impaired expression of mitochondrial and adipogenic genes in adipose tissue from a patient with acquired partial lipodystrophy (Barraquer-Simons syndrome): a case report

<p>Abstract</p> <p>Introduction</p> <p>Acquired partial lipodystrophy or Barraquer-Simons syndrome is a rare form of progressive lipodystrophy. The etiopathogenesis of adipose tissue atrophy in these patients is unknown.</p> <p>Case presentation</p> <p>This is a case report of a 44-year-old woman with acquired partial lipodystrophy. To obtain insight into the molecular basis of lipoatrophy in acquired partial lipodystrophy, we examined gene expression in adipose tissue from this patient newly diagnosed with acquired partial lipodystrophy. A biopsy of subcutaneous adipose tissue was obtained from the patient, and DNA and RNA were extracted in order to evaluate mitochondrial DNA abundance and mRNA expression levels.</p> <p>Conclusion</p> <p>The expression of marker genes of adipogenesis and adipocyte metabolism, including the master regulator <it>PPARγ</it>, was down-regulated in subcutaneous adipose tissue from this patient. Adiponectin mRNA expression was also reduced but leptin mRNA levels were unaltered. Markers of local inflammatory status were unaltered. Expression of genes related to mitochondrial function was reduced despite unaltered levels of mitochondrial DNA. It is concluded that adipogenic and mitochondrial gene expression is impaired in adipose tissue in this patient with acquired partial lipodystrophy.</p

Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample

<p>Abstract</p> <p>Background</p> <p>Common polymorphisms in the promoter of the <it>APOC3 </it>gene have been associated with hypertriglyceridemia and may impact on phenotypic expression of the metabolic syndrome (MetS). The rs7566605 marker, located near the <it>INSIG2 </it>gene, has been found to be associated with obesity, making it also a potential genetic determinant for MetS. The objective of this study is to examine the <it>APOC3 </it>-455T>C and the <it>INSIG2 </it>rs7566605 polymorphisms as potential genetic determinants for MetS in a multi-ethnic sample.</p> <p>Methods</p> <p>Subjects were genotyped for both the <it>APOC3 </it>-455T>C and <it>INSIG2 </it>rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (≥18 years of age) from six different geographical ancestries.</p> <p>Results</p> <p>For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of ≥1 copy of <it>APOC3 </it>-455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with <it>APOC3 </it>-455T>C genotype. The <it>INSIG2 </it>rs7566605 polymorphism was not associated with MetS or measures of obesity.</p> <p>Conclusion</p> <p>Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in <it>APOC3 </it>was associated with an approximately 2-fold increased risk of MetS, whereas the <it>INSIG2 </it>rs7566605 polymorphism was not associated with MetS.</p

The Impact of Augmented Information on Visuo-Motor Adaptation in Younger and Older Adults

BACKGROUND: Adjustment to a visuo-motor rotation is known to be affected by ageing. According to previous studies, the age-related differences primarily pertain to the use of strategic corrections and the generation of explicit knowledge on which strategic corrections are based, whereas the acquisition of an (implicit) internal model of the novel visuo-motor transformation is unaffected. The present study aimed to assess the impact of augmented information on the age-related variation of visuo-motor adjustments. METHODOLOGY/PRINCIPAL FINDINGS: Participants performed aiming movements controlling a cursor on a computer screen. Visual feedback of direction of cursor motion was rotated 75 degrees relative to the direction of hand motion. Participants had to adjust to this rotation in the presence and absence of an additional hand-movement target that explicitly depicted the input-output relations of the visuo-motor transformation. An extensive set of tests was employed in order to disentangle the contributions of different processes to visuo-motor adjustment. Results show that the augmented information failed to affect the age-related variations of explicit knowledge, adaptive shifts, and aftereffects in a substantial way, whereas it clearly affected initial direction errors during practice and proprioceptive realignment. CONCLUSIONS: Contrary to expectations, older participants apparently made no use of the augmented information, whereas younger participants used the additional movement target to reduce initial direction errors early during practice. However, after a first block of trials errors increased, indicating a neglect of the augmented information, and only slowly declined thereafter. A hypothetical dual-task account of these findings is discussed. The use of the augmented information also led to a selective impairment of proprioceptive realignment in the younger group. The mere finding of proprioceptive realignment in adaptation to a visuo-motor rotation in a computer-controlled setup is noteworthy since visual and proprioceptive information pertain to different objects

Aging syndrome genes and premature coronary artery disease

BACKGROUND: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. METHODS: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan(® )probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. RESULTS: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. CONCLUSION: Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO

Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD

BACKGROUND: Current evidence demonstrates that positive family history and several alterations in lipid metabolism are all important risk factors for coronary artery disease (CAD). All lipid abnormalities themselves have genetic determinants. Thus, objective of this study was to determine whether 6 genetic variants potentially related to altered lipid metabolism were associated with CAD and with lipid abnormalities in an Italian population. These genetic variables were: apolipoprotein E (Apo E), Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and the hepatic lipase (LIPC) genes. Furthermore, an 8 years prospective analysis of clinical cardiovascular events was related to the various genetic markers. METHODS: 102 subjects with established coronary artery disease and 104 unrelated normal subjects were studied. CAD Patients were followed up for 8 years, and clinical CAD outcomes (a second coronary angioplasty (PTCA), myocardial infarction, coronary artery by-pass graft (CABG), cardiovascular deaths), available from 60 subjects, were related to the genetic variants by multiple regression analysis. Results. Of the six lipid loci studied (for a total of 11 polymorphisms) only the apolipoprotein E, Apo B and LIPC polymorphisms distinguished between case and controls. However, multivariate analysis accounting for clinical and metabolic predictors of CAD showed that only the ApoB Xba1 and ApoE4 polymorphism associated with CAD in this Italian population. When lipid parameters were related to genotypes, the ApoE, ApoB, and LIPC gene polymorphisms were associated to various markers of dyslipidaemia in the CAD patients, confirming previous reports. When the occurrence of a second cardiovascular event was related to genotypes, an independent role was observed for the LIPC gene T202T variant. CONCLUSIONS: variation in LIPC (hepatic lipase) gene associates with clinical outcomes in Italian patients with established CAD. Further studies on the LIPC gene in CAD patients are warranted, in particular looking at the possible influences on clinical outcomes

Effect of the 3'APOB-VNTR polymorphism on the lipid profiles in the Guangxi Hei Yi Zhuang and Han populations

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein (Apo) B is the major component of low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and chylomicrons. Many genetic polymorphisms of the Apo B have been described, associated with variation of lipid levels. However, very few studies have evaluated the effect of the variable number of tandem repeats region 3' of the Apo B gene (3'APOB-VNTR) polymorphism on the lipid profiles in the special minority subgroups in China. Thus, the present study was undertaken to study the effect of the 3'APOB-VNTR polymorphism on the serum lipid levels in the Guangxi Hei Yi Zhuang and Han populations.</p> <p>Methods</p> <p>A total of 548 people of Hei Yi Zhuang were surveyed by a stratified randomized cluster sampling. The epidemiological survey was performed using internationally standardized methods. Serum lipid and apolipoprotein levels were measured. The 3'APOB-VNTR alleles were determined by polymerase chain reaction (PCR) followed by electrophoresis in polyacrylamide gels, and classified according to the number of repeats of a 15-bp hypervariable elements (HVE). The sequence of the most common allele was determined using the PCR and direct sequencing. The possible association between alleles of the 3'APOB-VNTR and lipid variables was examined. The results were compared with those in 496 people of Han who also live in that district.</p> <p>Results</p> <p>Nineteen alleles ranging from 24 to 64 repeats were detected in both Hei Yi Zhuang and Han. HVE56 and HVE58 were not be detected in Hei Yi Zhuang whereas HVE48 and HVE62 were totally absent in Han. The frequencies of HVE26, HVE30, HVE46, heterozygote, and short alleles (< 38 repeats) were higher in Hei Yi Zhuang than in Han. But the frequencies of HVE34, HVE38, HVE40, homozygote, and long alleles (≥ 38 repeats) were lower in Hei Yi Zhuang than in Han (<it>P </it>< 0.05–0.01). The levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and Apo B in Hei Yi Zhuang but not in Han were higher in VNTR-LS (carrier of one long and one short alleles) than in VNTR-LL (the individual carrying two long alleles) genotypes. The levels of TC, triglycerides (TG), LDL cholesterol, and Apo B in Hei Yi Zhuang were higher in both HVE34 and HVE36 alleles than in HVE32 allele. The levels of TC, TG, HDL-C and Apo B in Hei Yi Zhuang were also higher in homozygotes than in heterozygotes. There were no significant differences in the detected lipid parameters between the VNTR-SS (carrier of two short alleles) and VNTR-LS or VNTR-LL genotypes in both ethnic groups.</p> <p>Conclusion</p> <p>There were significant differences of the 3'APOB-VNTR polymorphism between the Hei Yi Zhuang and Han populations. An association between the 3'APOB-VNTR polymorphism and serum lipid levels was observed in the Hei Yi Zhuang but not in the Han populations.</p

A-6G and A-20C Polymorphisms in the Angiotensinogen Promoter and Hypertension Risk in Chinese: A Meta-Analysis

BACKGROUND: Numerous studies in Chinese populations have evaluated the association between the A-6G and A-20C polymorphisms in the promoter region of angiotensinogen gene and hypertension. However, the results remain conflicting. We carried out a meta-analysis for these associations. METHODS AND RESULTS: Case-control studies in Chinese and English publications were identified by searching the MEDLINE, EMBASE, CNKI, Wanfang, CBM, and VIP databases. The random-effects model was applied for dichotomous outcomes to combine the results of the individual studies. We finally selected 24 studies containing 5932 hypertensive patients and 5231 normotensive controls. Overall, we found significant association between the A-6G polymorphism and the decreased risk of hypertension in the dominant genetic model (AA+AG vs. GG: P=0.001, OR=0.71, 95%CI 0.57-0.87, P(heterogeneity)=0.96). The A-20C polymorphism was significantly associated with the increased risk for hypertension in the allele comparison (C vs. A: P=0.03, OR=1.14, 95%CI 1.02-1.27, P(heterogeneity)=0.92) and recessive genetic model (CC vs. CA+AA: P=0.005, OR=1.71, 95%CI 1.18-2.48, P(heterogeneity)=0.99). In the subgroup analysis by ethnicity, significant association was also found among Han Chinese for both A-6G and A-20C polymorphisms. A borderline significantly decreased risk of hypertension between A-6G and Chinese Mongolian was seen in the allele comparison (A vs. G: P=0.05, OR=0.79, 95%CI 0.62-1.00, P(heterogeneity)=0.84). CONCLUSION: Our meta-analysis indicated significant association between angiotensinogen promoter polymorphisms and hypertension in the Chinese populations, especially in Han Chinese

Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor–Null Mice With Diet-Induced Insulin Resistance

OBJECTIVE: The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance in vivo. RESEARCH DESIGN AND METHODS: LDL receptor-null (Ldlr(-/-)) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of insulin and glucose tolerance were determined. RESULTS: We report that naringenin treatment of Ldlr(-/-) mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha/PPARalpha-mediated transcription program; 2) prevented sterol regulatory element-binding protein 1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall insulin sensitivity and glucose tolerance. CONCLUSIONS: Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome

The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing

Recent whole-exome sequencing of malignancies have detected recurrent somatic mutations in U2 small nuclear ribonucleoprotein complex (snRNP) components of the spliceosome. These factors have also been identified as novel players in the DNA-damage response (DDR) in several genome-wide screens and proteomic analysis. Although accumulating evidence implies that the spliceosome has an important role in genome stability and is an emerging hallmark of cancer, its precise role in DNA repair still remains elusive. Here we identify two distinct mechanisms of how spliceosome U2 snRNP factors contribute to genome stability. We show that the spliceosome maintains protein levels of essential repair factors, thus contributing to homologous recombination repair. In addition, real-time laser microirradiation analysis identified rapid recruitment of the U2 snRNP factor SNRPA1 to DNA-damage sites. Functional analysis of SNRPA1 revealed a more immediate and direct role in preventing R-loop-induced DNA damage. Our present study implies a complex interrelation between transcription, mRNA splicing and the DDR. Cells require rapid spatio-temporal coordination of these chromatin transactions to cope with various forms of genotoxic stress