Browsing by Subject "Dyslipidemias"
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Item Diet-induced dyslipidemia drives store-operated Ca2+ entry, Ca2+ dysregulation, non-alcoholic steatohepatitis, and coronary atherogenesis in metabolic syndrome(2010-07-21T20:06:24Z) Neeb, Zachary P.; Sturek, Michael Stephen; Breall, Jeffrey A.; Considine, Robert V.; Obukhov, Alexander; Tune, Johnathan D.Risk of coronary artery disease (CAD), the leading cause of death, greatly increases in metabolic syndrome. Metabolic syndrome (MetS; obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension) is increasing in prevalence with sedentary lifestyles and poor nutrition. Non-alcoholic steatohepatitis (NASH; i.e. MetS liver) is progressive and decreases life expectancy, with CAD as the leading cause of death. Pathogenic Ca2+ regulation transforms coronary artery smooth muscle from a healthy, quiescent state to a diseased, proliferative phenotype thus majorly contributing to the development of CAD. In particular, store-operated Ca2+ entry (SOCE) in vascular smooth muscle is associated with atherosclerosis. Genetic predisposition may render individuals more susceptible to Ca2+ dysregulation, CAD, NASH, and MetS. However, the metabolic and cellular mechanisms underlying these disease states are poorly understood. Accordingly, the goal of this dissertation was to investigate the role of dyslipidemia within MetS in the development of Ca2+ dysregulation, CAD, and NASH. The overarching hypothesis was that dyslipidemia within MetS would be necessary for induction of NASH and increased SOCE that would primarily mediate development of CAD. To test this hypothesis we utilized the Ossabaw miniature swine model of MetS. Swine were fed one of five diets for different lengths of time to induce varying severity of MetS. Lean swine were fed normal maintenance chow diet. F/MetS swine were fed high Fructose (20% kcal) diet that induced normolipidemic MetS. TMetS were fed excess high Trans-fat/cholesterol atherogenic diet that induced mildly dyslipidemic MetS and CAD. XMetS were TMetS swine with eXercise. DMetS (TMetS + high fructose) were moderately dyslipidemic and developed MetS and extensive CAD. sDMetS (Short-term DMetS) developed MetS with mild dyslipidemia, but no CAD. MMetS (Mixed-source-fat/cholesterol/fructose) were severely dyslipidemic, exhibited NASH, and developed severe CAD. Dyslipidemia in MetS predicted NASH severity (all groups < DMetS << MMetS), CAD severity (i.e. Lean, F/MetS, sDMetS < XMetS < TMetS < DMetS < MMetS), and was necessary for STIM1/TRPC1-mediated SOCE, which preceded CAD. Exercise ameliorated SOCE and CAD compared to TMetS. In conclusion, dyslipidemia elicits TRPC1/STIM1 SOCE that mediates CAD, is necessary for and predictive of NASH and CAD, and whose affects are attenuated by exercise.Item Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy.(Elsevier, 2016-09) Wang, Qi; Navitskaya, Svetlana; Chakravarthy, Harshini; Huang, Chao; Kady, Nermin; Lydic, Todd A.; Chen, Y. Eugene; Yin, Ke-Jie; Powell, Folami Lamoke; Martin, Pamela M.; Grant, Maria B.; Busik, Julia V.; Department of Ophthalmology, IU School of MedicineActivation of pro-inflammatory and pro-angiogenic pathways in the retina and the bone marrow contributes to pathogenesis of diabetic retinopathy. We identified miR-15a as key regulator of both pro-inflammatory and pro-angiogenic pathways through direct binding and inhibition of the central enzyme in the sphingolipid metabolism, ASM, and the pro-angiogenic growth factor, VEGF-A. miR-15a was downregulated in diabetic retina and bone marrow cells. Over-expression of miR-15a downregulated, and inhibition of miR-15a upregulated ASM and VEGF-A expression in retinal cells. In addition to retinal effects, migration and retinal vascular repair function was impaired in miR-15a inhibitor-treated circulating angiogenic cells (CAC). Diabetic mice overexpressing miR-15a under Tie-2 promoter had normalized retinal permeability compared to wild type littermates. Importantly, miR-15a overexpression led to modulation toward nondiabetic levels, rather than complete inhibition of ASM and VEGF-A providing therapeutic effect without detrimental consequences of ASM and VEGF-A deficiencies.Item Pubertal maturation and weight status are associated with dyslipidemia among children and adolescents in Northwest China(Nature Publishing Group, 2020-10-01) Cao, Juan; Zhang, Ling; Li, Jing; Sun, Lijiao; Liu, Shanghong; Zhang, Jianjun; Zhao, Haiping; Epidemiology, School of Public HealthDyslipidemia is one of major risk factors for cardiovascular disease. The early detection and treatment of dyslipidemia can reduce cardiovascular disease risk. A cross-sectional study was carried out in Ningxia, China to determine the prevalence of dyslipidemia and its association with body mass index (BMI) and pubertal stage. A total of 1783 students were selected from middle schools and high schools in September 2014 using stratified random cluster sampling. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured by using MOL-300 automatic biochemical analyzer with associated kits. The prevalence of adolescents with one abnormal serum lipid component was 43.2% and was significantly different across three pubertal stages (p < 0.0001). The abnormal rates of HDL-C and TG increased as the students maturated through the early, middle, and late stages of puberty (all p < 0.0001). Similar results were obtained when separate analyses were performed for boys and girls. In linear regression analysis, BMI was positively associated with serum levels of TC, LDL-C, and TG, but inversely associated with serum levels of HDL-C after the adjustment for age, sex, and race. In multivariable logistic regression analysis, obesity was associated with an increased risk of developing high TC, while pubertal maturation was associated with an elevated risk of experiencing low HDL-C and high TG (all p < 0.05). In conclusions, dyslipidemia is common in an adolescent population of Northwest China and its prevalence rates substantially vary with weight status and pubertal stage.Item Role of Acid Sphingomyelinase in Shifting the Balance Between Proinflammatory and Reparative Bone Marrow Cells in Diabetic Retinopathy(Wiley, 2016-04) Chakravarthy, Harshini; Navitskaya, Svetlana; O'reilly, Sandra; Gallimore, Jacob; Mize, Hannah; Beli, Eleni; Wang, Qi; Kady, Nermin; Huang, Chao; Blanchard, Gary J.; Grant, Maria B.; Busika, Julia V.; Ophthalmology, School of MedicineThe metabolic insults associated with diabetes lead to low-grade chronic inflammation, retinal endothelial cell damage, and inadequate vascular repair. This is partly due to the increased activation of bone marrow (BM)-derived proinflammatory monocytes infiltrating the retina, and the compromised function of BM-derived reparative circulating angiogenic cells (CACs), which home to sites of endothelial injury and foster vascular repair. We now propose that a metabolic link leading to activated monocytes and dysfunctional CACs in diabetes involves upregulation of a central enzyme of sphingolipid signaling, acid sphingomyelinase (ASM). Selective inhibition of ASM in the BM prevented diabetes-induced activation of BM-derived microglia-like cells and normalized proinflammatory cytokine levels in the retina. ASM upregulation in diabetic CACs caused accumulation of ceramide on their cell membrane, thereby reducing membrane fluidity and impairing CAC migration. Replacing sphingomyelin with ceramide in synthetic membrane vesicles caused a similar decrease in membrane fluidity. Inhibition of ASM in diabetic CACs improved membrane fluidity and homing of these cells to damaged retinal vessels. Collectively, these findings indicate that selective modulation of sphingolipid metabolism in BM-derived cell populations in diabetes normalizes the reparative/proinflammatory cell balance and can be explored as a novel therapeutic strategy for treating diabetic retinopathy.Item Selenium Level and Dyslipidemia in Rural Elderly Chinese(Public Library of Science, 2015) Su, Liqin; Gao, Sujuan; Unverzagt, Frederick W.; Cheng, Yibin; Hake, Ann M.; Xin, Pengju; Chen, Chen; Liu, Jingyi; Ma, Feng; Bian, Jianchao; Li, Ping; Jin, Yinlong; Department of Biostatistics, School of Public HealthOBJECTIVE: Higher selenium level has been hypothesized to have the potential to reduce the risk of cardiovascular diseases including dyslipidemia. However, results from previous studies are inconsistent. This study aims to determine the association between selenium level and dyslipidemia in elderly Chinese with relatively low selenium status. METHODS: A cross-sectional study of 1859 participants aged 65 or older from four rural counties in China was conducted. Serum total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDLC) and low-density lipoprotein-cholesterol (LDLC), nail selenium concentration and APOE genotype were measured in all subjects. The four types of dyslipidemia were defined as >5.17 mmol/L for High-TC, >1.69 mmol/L for High-TG, >3.36 mmol/L for High-LDLC, and <1.04 mmol/L for Low-HDLC according to Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults. Logistic models adjusting for age, gender, APOE genotype, body mass index, alcohol consumption, smoking, physical activity, medication use for cardiovascular diseases were used to examine the relationship between selenium levels and the risk of dyslipidemia. RESULTS: Mean nail selenium concentration was 0.465 μg/gin this sample. Rates for High-TC, High-LDLC, High-TG, Low-HDLC were 18.13%, 13.23%, 12.21% and 32.76% respectively. Results from logistic models indicated that higher selenium levels were significantly associated with higher risk of High-TC, High-LDLC and lower risk of Low-HDLC adjusting for covariates (p < 0.0001). Compared with the lowest selenium quartile group, participants in selenium quartile groups 2, 3 and 4 had significantly higher rates of High-TC, High-LDLC, High-TG, and lower rate of Low-HDLC adjusting for covariates. No significant association was observed between selenium level and the risk of High-TG. APOEε4 carriers had higher rates of High-TC and High-LDLC. There was no interaction between selenium level and APOE with the rates of dyslipidemia. CONCLUSIONS: Our results suggest long-term selenium exposure level may be associated with the risk of dyslipidemia in elderly population. Future studies are needed to examine the underlying mechanism of the association.Item Sets of coregulated serum lipids are associated with Alzheimer's disease pathophysiology(Elsevier, 2019-09-05) Barupal, Dinesh Kumar; Baillie, Rebecca; Fan, Sili; Saykin, Andrew J.; Meikle, Peter J.; Arnold, Matthias; Nho, Kwangsik; Fiehn, Oliver; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineIntroduction: Comorbidity with metabolic diseases indicates that lipid metabolism plays a role in the etiology of Alzheimer's disease (AD). Comprehensive lipidomic analysis can provide new insights into the altered lipid metabolism in AD. Method: In this study, a total 349 serum lipids were measured in 806 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative Phase 1 cohort and analyzed using lipid-set enrichment statistics, a data mining method to find coregulated lipid sets. Results: We found that sets of blood lipids were associated with current AD biomarkers and with AD clinical symptoms. AD diagnosis was associated with 7 of 28 lipid sets of which four also correlated with cognitive decline, including polyunsaturated fatty acids. Cerebrospinal fluid amyloid beta (Aβ1-42) correlated with glucosylceramides, lysophosphatidylcholines and unsaturated triacylglycerides; cerebrospinal fluid total tau and brain atrophy correlated with monounsaturated sphingomyelins and ceramides, in addition to EPA-containing lipids. Discussion: AD-associated lipid sets indicated that lipid desaturation, elongation, and acyl chain remodeling processes are disturbed in AD subjects. Monounsaturated lipid metabolism was important in early stages of AD, whereas the polyunsaturated lipid metabolism was associated with later stages of AD. Our study provides several new hypotheses for studying the role of lipid metabolism in AD.