Yoonsu Cho

Quercetin up-regulates expressions of peroxisome proliferator-activated receptor γ, liver X receptor α, and ATP binding cassette transporter A1 genes and increases cholesterol efflux in human macrophage cell line

Cholesterol-laden macrophages trigger accumulation of foam cells and increase the risk of developing atherosclerosis. We hypothesized that quercetin could lower the content of cholesterol in macrophages by regulating the expression of the ATP binding cassette transporter A1 (ABCA1) gene in differentiated human acute monocyte leukemia cell line (THP-1) cells and thereby reducing the chance of forming foam cells. Quercetin, in concentrations up to 30 μM, was not cytotoxic to differentiated THP-1 cells. Quercetin up-regulated both ABCA1 messenger RNA and protein expression in differentiated THP-1 cells, and its maximum effects were demonstrated at 0.3 μM for 4 to 8 hours in incubation. In addition, quercetin increased protein levels of peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) within 2 hours of treatment. Because PPARγ and LXRα are important transcriptional factors for ABCA1, quercetin-induced up-regulation of ABCA1 may be mediated by increased expression levels of the PPARγ and LXRα genes. Furthermore, quercetin-enhanced cholesterol efflux from differentiated THP-1 cells to both high-density lipoprotein (HDL) and apolipoprotein A1. Quercetin at the dose of 0.15 μM elevated the cholesterol efflux only for HDL. At the dose of 0.3 μM, quercetin demonstrated effects both on HDL and apolipoprotein A1. Our data demonstrated that quercetin increased the expressions of PPARγ, LXRα, and ABCA1 genes and cholesterol efflux from THP-1 macrophages. Quercetin-induced expression of PPARγ and LXRα might subsequently affect up-regulation of their target gene ABCA1. Taken together, ingestion of quercetin or quercetin-rich foods could be an effective way to improve cholesterol efflux from macrophages, which would contribute to lowering the risk of atherosclerosis.

Alcohol intake and cardiovascular risk factors: A Mendelian randomisation study

Mendelian randomisation studies from Asia suggest detrimental influences of alcohol on cardiovascular risk factors, but such associations are observed mainly in men. The absence of associations of genetic variants (e.g. rs671 in ALDH2) with such risk factors in women – who drank little in these populations – provides evidence that the observations are not due to genetic pleiotropy. Here, we present a Mendelian randomisation study in a South Korean population (3,365 men and 3,787 women) that 1) provides robust evidence that alcohol consumption adversely affects several cardiovascular disease risk factors, including blood pressure, waist to hip ratio, fasting blood glucose and triglyceride levels. Alcohol also increases HDL cholesterol and lowers LDL cholesterol. Our study also 2) replicates sex differences in associations which suggests pleiotropy does not underlie the associations, 3) provides further evidence that association is not due to pleiotropy by showing null effects in male non-drinkers, and 4) illustrates a way to measure population-level association where alcohol intake is stratified by sex. In conclusion, population-level instrumental variable estimation (utilizing interaction of rs671 in ALDH2 and sex as an instrument) strengthens causal inference regarding the largely adverse influence of alcohol intake on cardiovascular health in an Asian population.

Quercetin Up‐regulates LDL Receptor Expression in HepG2 Cells

Quercetin, an abundant flavonol found in fruits and vegetable, has been implicated in lowering the risk of cardiovascular disease that is often associated with high plasma levels of low density lipoprotein (LDL) cholesterol. Here we investigated whether quercetin could modulate the expression of LDL receptors (LDLR) in HepG2 cells and the possible underlying mechanisms to exert quercetins effects. We found that quercetin was able to induce LDLR expression with at least a 75 µ m concentration, which was accompanied by an increase in nuclear sterol regulatory element binding protein 2 (SREBP2). This effect was mediated by activation of c‐jun‐N‐terminal kinase (JNK) and extracellular signal‐regulated kinase (ERK) signalling pathways as implicated by experiments using chemical inhibitors of each pathway. When cells were challenged with protein synthesis inhibitors in quercetin‐activated LDLR transcription, LDL mRNA levels were not significantly affected by cycloheximide but puromycin abolished quercetin‐induced LDLR transcription. Taken together, we conclude that quercetin can initiate LDLR transcription by enhancing SREBP2 processing, but new protein synthesis might be necessary to exert a maximum effect of quercetin in the up‐regulation of the LDLR gene. Our findings demonstrate that quercetin strongly up‐regulated LDLR gene expression, which might elicit hypolipidemic effects by increasing the clearance of circulating LDL cholesterol levels from the blood. Copyright

Plasma phospholipid fatty acid composition in ischemic stroke: Importance of docosahexaenoic acid in the risk for intracranial atherosclerotic stenosis

OBJECTIVE While data on the relationship between fatty acid (FA) composition and the risk for total stroke have accumulated, the association between FA composition and the risk for intracranial atherosclerotic stenosis (ICAS) has never been studied. We compared plasma phospholipid FA composition between non-stroke control and ischemic stroke in Korean population, to discern the FA that distinguishes ICAS from total ischemic stroke patients. METHODS Non-stroke controls (n = 215) and stroke patients (no cerebral atherosclerotic stenosis, NCAS: n = 144 and ICAS: n = 104) were finally included in the analysis. Plasma phospholipid FA compositions were analyzed. RESULTS Age, coexistence of hypertension/diabetes were significantly different among the groups. Phospholipid FA compositions were significantly different between non-stroke control and ischemic stroke patients, and interestingly, between NCAS and ICAS in stroke patients. Pattern analysis showed that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the ω3-polyunsaturated FAs were important FAs in distinguishing NCAS and ICAS in strokes. Particularly, the risk of ICAS was inversely associated with levels of DHA contents in phospholipids (OR: 0.590, 95% CI: 0.350-0.993, p < 0.05), indicating that the risk may be increased at lower levels of DHA contents. CONCLUSION DHA and EPA are important FAs for distinguishing NCAS and ICAS in strokes. Additionally, the risk of ICAS was inversely associated with the levels of phospholipid DHA, which indicates that sufficient amounts of DHA in plasma or in diet may reduce the risk of ICAS.

The association between serum 25-hydroxyvitamin D concentrations and depressive symptoms in Korean adults: findings from the fifth Korea National Health and Nutrition Examination Survey 2010.

The aims of this study were to examine the association between circulating vitamin D (25(OH)D) levels and depressive symptoms and to evaluate the associations between depressive symptoms and various sociodemographic factors. Data on serum 25(OH)D levels, sociodemographic factors, and information on depressive symptoms were obtained from the Korea National Health and Nutrition Examination Survey V-1 2010. A total of 3,570 Koreans aged ≥20 years were included in the statistical analysis. Subjects with depressive symptoms had lower serum levels of 25(OH)D (41.6±16.2 nmol/L) than those without (44.3±16.2 nmol/L; P-value<0.05; effect size = 0.17). In a logistic regression analysis, the 25(OH)D sufficiency group (≥50 nmol/L) revealed fewer depressive symptoms (OR, 0.72; 95% CI, 0.53–0.97; P-value = 0.032) after adjusting for multiple factors. In addition, females (OR, 3.61; 95% CI, 2.55–5.11; P-value<0.001), problematic alcohol users (OR, 2.33; 95% CI, 1.63–3.34; P-value<0.001), current smokers (OR, 1.43; 95% CI, 1.02–1.99; P-value = 0.036), and subjects who experienced weight loss (OR, 1.78; 95% CI, 1.30–2.44; P-value<0.001) were more likely to answer “yes” on question for depressive symptoms. In conclusion, low serum levels of 25(OH)D were associated with an increased risk for depression symptoms in Korean adults. In addition, several sociodemographic factors were related to the depressive symptoms. Our results provide insight into the relationships among vitamin D status, sociodemographic factors, and depression in the Korean population.

Sarcopenic obesity is associated with lower indicators of psychological health and quality of life in Koreans

Sarcopenic obesity (SO) is known to contribute to morbidity and mortality from chronic diseases. However, there exists limited information regarding its effect on psychological health. The aim of this study was to evaluate association of SO with several indices of psychological health and quality of life (QoL) in Korean adults. This cross-sectional study was conducted with 11521 participants older than 20 years from the Korea National Health and Nutrition Examination Survey 2008-2011. Sarcopenic obesity was defined by a low appendicular skeletal muscle mass divided by body weight less than 1 standard deviation below the sex-specific mean for the young reference group, and by a high waist circumference of at least 90 cm for men and at least 85 cm for women. Psychological health status, including depressive symptoms, perceived stress, and suicidal ideation, as well as QoL, was assessed by a self-reporting questionnaire. Association between SO and psychological health status was assessed under a logistic regression model. After multivariate adjustment for demographics and lifestyle factors, SO was significantly associated with perceived stress (odds ratio, 1.24; 95% confidence interval, 1.07-1.44; P value = .004) and suicidal ideation (odds ratio, 1.26; 95% confidence interval, 1.06-1.50; P value = .010). In addition, SO was found to have a negative association with a range of QoL indicators. Interestingly, these association patterns were more significant in participants younger than 60 years. In conclusion, our results suggest that SO was associated with adverse psychological health and lower QoL more than body mass index-based general obesity.

Arginase Inhibition Ameliorates Hepatic Metabolic Abnormalities in Obese Mice

Objectives We examined whether arginase inhibition influences hepatic metabolic pathways and whole body adiposity in diet-induced obesity. Methods and Results After obesity induction by a high fat diet (HFD), mice were fed either the HFD or the HFD with an arginase inhibitor, Nω-hydroxy-nor-L-arginine (nor-NOHA). Nor-NOHA significantly prevented HFD-induced increases in body, liver, and visceral fat tissue weight, and ameliorated abnormal lipid profiles. Furthermore, nor-NOHA treatment reduced lipid accumulation in oleic acid-induced hepatic steatosis in vitro. Arginase inhibition increased hepatic nitric oxide (NO) in HFD-fed mice and HepG2 cells, and reversed the elevated mRNA expression of hepatic genes in lipid metabolism. Expression of phosphorylated 5′ AMPK-activated protein kinase α was increased by arginase inhibition in the mouse livers and HepG2 cells. Conclusions Arginase inhibition ameliorated obesity-induced hepatic lipid abnormalities and whole body adiposity, possibly as a result of increased hepatic NO production and subsequent activation of metabolic pathways involved in hepatic triglyceride metabolism and mitochondrial function.

Effects of fisetin supplementation on hepatic lipogenesis and glucose metabolism in Sprague–Dawley rats fed on a high fat diet

The modulatory effects of daily fisetin supplementation for 8 weeks on genes involved in hepatic lipogenesis and gluconeogenesis and hyperglycemia in rats fed a high fat (HF) diet were evaluated. Elevated levels of triglyceride (TG), along with hepatic TG content and glucose concentrations in a high fat diet group were found to be reduced by fisetin supplementation. The high fat diet significantly increased hepatic mRNA expressions of PPARγ, SREBP1C and SCD-1 genes in comparison to the control diet, which was subsequently reversed by supplementation with fisetin. In addition, fisetin supplementation significantly reduced hepatic mRNA abundance of FAS, ATPCL and G6Pase compared to the control group. Finally, epididymal mRNA abundance of GLUT4 was significantly increased by fisetin supplementation, compared to levels in the control and HF groups. Enhancement of GLUT4 expression by fisetin was further confirmed in differentiated 3T3-L1 adipocytes. Fisetin supplementation decreases cardiovascular risks by ameliorating hepatic steatosis and lowering circulating glucose concentrations.

Alcohol Use Behaviors, Fat Intake and the Function of Pancreatic β-Cells in Non-Obese, Healthy Korean Males: Findings from 2010 Korea National Health and Nutrition Examination Survey

Aims: In the present study, we aimed to identify dietary factors related to insulin secretion function especially in healthy, non-obese Korean males. Methods: Data were obtained from the Korea National Health and Nutrition Examination Survey V-1 (KNHANES V-1). Nine hundred and twenty male adults aged >30 years of normal weight were included, excluding those with type 2 diabetes mellitus and liver disease. Alcohol use disorders identification test (AUDIT) score which represents alcohol use behaviors and nutrient intakes was used, and homeostasis model assessment of β-cell function (HOMA-B score) was calculated. Results: HOMA-B score was associated with age (p < 0.001), AUDIT score (p = 0.030), and percentage of fat from total energy intake (p = 0.002). HOMA-B scores in the problematic AUDIT group were significantly lower than those in the normal AUDIT group. In addition, HOMA-B scores in the lowest fat intake group were significantly lower than those in the medium fat intake group, but similar to those in the highest fat intake group. There was an interaction between alcohol use behaviors and percentage of fat from energy intake in determining HOMA-B score (p for interaction = 0.034). Conclusions: Alcohol use behaviors and percentage of fat from energy intake were found to be associated with HOMA-B score in healthy, non-obese Korean males.

Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study

Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here, we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Data were collected from 7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene region as an instrument, one unit of GGT levels (IU/L) was associated with 11% higher risk of type 2 diabetes (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.04 to 1.19). In a multiple IV analysis using seven genetic variants that have previously been demonstrated to be associated with GGT at a genome-wide level of significance, the corresponding estimate suggested a 2.6% increase in risk (OR = 1.026, 95% CI: 1.001 to 1.052). In a two-sample Mendelian randomization analysis using genetic associations with type 2 diabetes taken from a trans-ethnic GWAS study of 110 452 independent samples, the single IV analysis confirmed an association between the rs4820599 and type 2 diabetes risk (P-value = 0.04); however, the estimate from the multiple IV analysis was compatible with the null (OR = 1.007, 95% CI: 0.993 to 1.022) with considerable heterogeneity between the causal effects estimated using different genetic variants. Overall, there is weak genetic evidence that GGT levels may have a causal role in the development of type 2 diabetes.