Jihyun Song

National Institute of Health, Korea, Seishō-gun, North Gyeongsang, South Korea

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Publications (39)107.57 Total impact

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    ABSTRACT: Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (GCK) nitration and downregulation, leading to impaired glucose tolerance and insulin resistance; but the underlying mechanism remain largely unknown. Here, we demonstrate that GCK gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro; whereas expression of activating transcription factor 3 (ATF3) and its binding to the putative ATF/CREB site (from -287 bp to -158 bp) on GCK promoter were upregulated. Furthermore, in vitro ethanol-induced ATF3 inhibited the positive effect of PDX-1 on GCK transcriptional regulation, enhanced recruitment of HDAC1/2 and histone H3 deacetylation, and subsequently augmented the interaction of HDAC1/PDX-1 on the GCK promoter, which were diminished by ATF3 siRNA. Corroboratory, in vivo ATF3-silencing reversed ethanol-mediated GCK downregulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified ethanol-induced ATF3 fosters β-cell dysfunction via GCK downregulation and that its loss ameliorates metabolic syndromes and could be a potential therapeutic target in treating T2D. And also, ATF3 gene is associated with the induction of T2D and alcohol consumption-induced metabolic impairment and thus may play as the major negative regulator for glucose homeostasis.
    The Journal of biological chemistry. 07/2014;
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    ABSTRACT: Objectives An increase in serum ferritin and levels of the cleaved soluble form of the receptor (sTfR) are related to several metabolic conditions. We evaluated the relationship between body iron status indicators, including ferritin and sTfR, and insulin resistance and metabolic syndrome (MetS) in Korean children. Methods A cross-sectional study was conducted on 1350 children in Korea. Anthropometrical parameters; lipid profiles; levels of glucose, insulin, and leptin; and iron status indicators, including sTfR, serum ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TS), were analyzed. Results While serum sTfR levels were significantly higher in boys than in girls (2.20 vs. 2.06 mg/l, p < 0.0001), serum iron and TS were higher in girls than in boys (101.38 vs. 95.77 mg/l, p = 0.027 and 30.15 vs. 28.91%, p = 0.04, respectively). Waist circumference (WC) and leptin were most significantly associated with body iron indicators when adjusted for age and sex. After adjusting for age, sex, and WC, sTfR levels showed the strongest positive association with leptin levels (p = 0.0001). Children in the highest tertile for HOMA-IR had higher TIBC (p = 0.0005) and lower serum iron (p = 0.0341).and the lowest TS (p < 0.0001) after adjustment for confounders. Children with higher sTfR were most significantly associated with risk of MetS compared with those lower (p = 0.0077). Conclusion The associations of serum levels of iron metabolism markers with leptin levels, HOMA-IR, and MetS suggest that iron-related factors may involve to insulin resistance and metabolic syndrome.
    Osong Public Health and Research Perspectives. 01/2014;
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    ABSTRACT: Purpose Obesity in youth increases the risk of obesity in adulthood, and is predictive of the development of metabolic disorders. The fatty acid compositions of various tissues, including blood, are associated with obesity and obesity-associated disorders. Thus, tracking plasma phospholipid features and metabolic parameters in young subjects may strengthen the utility of fatty acid composition as an early biomarker of future metabolic disorders. Method Anthropometric and blood biochemical data were obtained from 131 Korean males aged 10.5 ± 0.4 years, and followed up at 2 years. We analyzed the plasma phospholipid fatty acid according to obesity. Obese children were defined as those with a BMI greater than the 85th percentile for age and gender, based on Korean child growth standards. Results Activities of lipid desaturases, stearyl-CoAD (SCD-16,16:1n-7/16:0), delta-6D (D6D, 20:3n-6/18:2n-6), and delta-5D (D5D, 20:4n-6/20:3n-6), were estimated. Obese subjects had significantly higher proportions of palmitoleic acid (16:1n-7) and dihomo-gamma linolenic acid (DGLA, 20:3n-6) at both baseline and follow-up than did lean subjects. The activities of SCD-16 and D6D were higher in obese than lean boys. The baseline SCD-16 activity level was positively associated with the baseline waist circumference (WC) and the metabolic risk score. The baseline D6D level was positively associated with WC and also with the homeostasis model of assessment of insulin resistance, a surrogate marker of insulin resistance, and metabolic risk score at both baseline and follow-up. Conclusion In young Korean males, higher D6D activity predicts the future development of insulin resistance and associated metabolic disorders including dyslipidemia.
    Osong Public Health and Research Perspectives. 01/2014;
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    ABSTRACT: Several association studies have implicated the PARK2 gene that encodes parkin - the key molecule orchestrating the mitochondrial quality control system - as a candidate susceptibility gene for diabetes. A total of 7,551 unrelated Korean KARE cohort subjects were analyzed to investigate the association between the PARK2 single nucleotide polymorphism (SNP) and quantitative glycemic traits. Two SNPs, rs10455889 and rs9365294, were significantly associated with fasting plasma glucose level (p=∼1.2×10(-4)) and insulin secretion indices (p=∼7.4×10(-5)) in male KARE subjects. Parkin was expressed predominantly in the rat pancreatic islets. Downregulation of the Park2 gene in rat INS-1 β-cells resulted in a significant decrease in the glucose-stimulated insulin secretion, intracellular insulin gene expression, and intracellular ATP level. The Park2-depleted β-cells also exhibited increased mitochondrial fragmentation and ROS production and decreased mitochondrial membrane potential. Both population-based statistical evaluation and experimental evidence demonstrated a fundamental role of the PARK2 gene in the maintenance of β-cell function.
    Molecular and Cellular Endocrinology 10/2013; · 4.04 Impact Factor
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    ABSTRACT: Liver enzyme elevations, as an indicator of liver function, are widely associated with metabolic diseases. Genome-wide population-based association studies have identified a genetic susceptibility to liver enzyme elevations and their related traits; however, the genetic architecture in childhood remains largely unknown. We performed a genome-wide association study to identify new genetic loci for liver enzyme levels in a Korean childhood cohort (n = 484). We observed three novel loci (rs4949718, rs80311637, and rs596406) that were multiply associated with elevated levels of alanine transaminase and aspartate transaminase. Although there are some limitations, including genetic power, additional replication and functional characterization will support the clarity on the genetic contribution that the ST6GALNAC3, ADAMTS9, and CELF2 genes have in childhood liver function.
    Genomics & informatics. 09/2013; 11(3):149-154.
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    ABSTRACT: In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic β-cell dysfunction; however the exact mechanisms by which ER stress drives type-2 diabetes remain uncertain. Here, we investigated the role of ATF3 on the preventive regulation of AMPK against ER stress-mediated β-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and β-cell dysfunction were significantly increased in late-diabetic phase 19-week-old ZDF rats. Although AMPK phosphorylation reduced in 6- and 12-week-old ZDF rats was remarkably increased at 19weeks, the increases of lipogenice genes, ATF3, and ER stress or ROS-mediated β-cell dysfunction were still remained, which were attenuated by in vivo-injection of chemical chaperon tauroursodeoxycholate (TUDCA), chronic AICAR, or antioxidants. ATF3 did not directly affect AMPK phosphorylation, but counteracts the preventive effects of AMPK for high glucose-induced β-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated β-cell dysfunction and enhanced the beneficial effect of AICAR. Our data suggest that ATF3 may play as a counteracting regulator of AMPK and thus promote β-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes.
    Cellular signalling 08/2013; · 4.09 Impact Factor
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    ABSTRACT: Vitamin D, a key regulator of bone metabolism, has been recently been linked with energy homeostasis and metabolic disorders in western countries. However, few studies have focused on the association of vitamin D with metabolic risk factors among Asian children. We studied the prevalence of vitamin D insufficiency and the association of 25-hydroxyvitamin D [25(OH)D] with metabolic risk factors in Korean schoolgirls. The sample consisted of 320 13-year-old girls recruited from two middle schools in the city of Gwacheon, Korea (latitude 37°N), in July 2011. Anthropometric and blood biochemistry data were obtained for this cross-sectional observational study. We also obtained lifestyle data from questionnaires and dietary data from 3-day food diaries. Vitamin D deficiency [25(OH)D < 20 ng/mL] was noted in 63.8% of participants. The mean 25(OH)D level was not significantly lower in the overweight group. Level of physical activity and vitamin D intake did not significantly affect 25(OH)D. However, 25(OH)D levels were positively correlated with milk intake and negatively correlated with soft drink intake. Serum 25(OH)D had a negative relationship with fasting glucose and insulin resistance index (homeostasis model assessment-insulin resistance; HOMA-IR) after adjustment for physical activity and body mass index z score (r = -0.144, p = 0.015), and with metabolic risk score similarly (r = -0.141, p = 0.012). Levels of insulin, HOMA-IR, and systolic blood pressure were higher in girls with deficient 25(OH)D levels than in those with sufficient levels. We found that low 25(OH)D levels were associated with higher blood glucose and insulin resistance. Korean girls with low 25(OH)D levels could be at increased risk for metabolic disorders.
    Osong public health and research perspectives. 08/2013; 4(4):179-86.
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    ABSTRACT: PURPOSE: Diets rich in fat and energy are associated with metabolic syndrome (MS). Increased body iron stores have been recognized as a feature of MS. High-fat diets (HFs), excess iron loading and MS are closely associated, but the mechanism linking them has not been clearly defined. We investigated the interaction between dietary fat and dietary Fe in the context of glucose and lipid metabolism in the body. METHODS: C57BL6/J mice were divided into four groups and fed the modified AIN-93G low-fat diet (LF) and HF with adequate or excess Fe for 7 weeks. The Fe contents were increased by adding carbonyl iron (2% of diet weight) (LF+Fe and HF+Fe). RESULTS: High iron levels increased blood glucose levels but decreased high-density lipoprotein cholesterol levels. The HF group showed increases in plasma levels of glucose and insulin and insulin resistance. HF+Fe mice showed greater changes. Representative indices of iron status, such hepatic and plasma Fe levels, were not altered further by the HF. However, both the HF and excess iron loading changed the hepatic expression of hepcidin and ferroportin. The LF+Fe, HF and HF+Fe groups showed greater hepatic fat accumulation compared with the LF group. These changes were paralleled by alterations in the levels of enzymes related to hepatic gluconeogenesis and lipid synthesis, which could be due to increases in mitochondrial dysfunction and oxidative stress. CONCLUSIONS: High-fat diets and iron overload are associated with insulin resistance, modified hepatic lipid and iron metabolism and increased mitochondrial dysfunction and oxidative stress.
    The Journal of nutritional biochemistry 05/2013; · 4.29 Impact Factor
  • Joo Sun Choi, In-Uk Koh, Jihyun Song
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    ABSTRACT: Postmenopausal women are at higher risk for obesity and insulin resistance due to the decline of estrogen, but genistein, a phytoestrogen, may reduce the risks of these diet-related diseases. In this study, we hypothesized that supplemental genistein has beneficial effects on insulin resistance in an ovariectomized rat model by modulating lipid metabolism. Three weeks after a sham surgery (sham) or an ovariectomy (OVX), ovariectomized Sprague-Dawley rats were placed on a diet containing 0 (OVX group) or 0.1% genistein for 4 weeks. The sham rats were fed a high-fat diet containing 0% genistein and served as the control group (sham group). The ovariectomized rats showed increases in body weight and insulin resistance index, but genistein reduced insulin resistance index and the activity of hepatic fatty acid synthetase. Genistein was also associated with increased activity of succinate dehydrogenase and carnitine palmitoyltransferase and the rate of β-oxidation in the fat tissue of rats. The ovariectomized rats given genistein had smaller-sized adipocytes. Using gene-set enrichment analysis (GSEA) of microarray data, we found that a number of gene sets of fatty acid metabolism, insulin resistance, and oxidative stress were differentially expressed by OVX and reversed by genistein. This systemic approach of GSEA enables the identification of such consensus between the gene expression changes and phenotypic changes caused by OVX and genistein supplementation. Genistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance.
    Nutrition research (New York, N.Y.) 11/2012; 32(11):844-55. · 1.20 Impact Factor
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    ABSTRACT: To investigate the role of genetic predisposition in the pathogenesis of polycystic ovary syndrome (PCOS) in relation to obesity, we performed a genome-wide association study of PCOS in Koreans (n=1741). PCOS is a heterogeneous endocrinal disorder of uncertain etiology. Obesity is one of the well-known risk factors for PCOS. Genome-wide association study. Women with or without PCOS. A total of 1881 samples were genotyped using Illumina HumanOmni1 Quad v1 and processed by R packages. The PCOS patients were divided into two subgroups according to PCOS diagnostic criteria (Rotterdam and National Institutes of Health (NIH)). For PCOS-associated loci in the two definitions, we successfully confirmed significant associations of GYS2 for body mass index in the discovery stage. We further replicated pleiotropic associations of GYS2 in a childhood obesity study (n=482) and in a gestational diabetes study (n=1710), respectively. Our study provides a preliminary framework upon diverse genetic effects underlying PCOS in Korean women. A newly identified GYS2 gene as a predisposing factor of PCOS might expand understanding of the biological pathways in metabolic and endocrine regulation.
    Journal of Human Genetics 09/2012; 57(10):660-4. · 2.37 Impact Factor
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    ABSTRACT: Dyslipidemia, mainly characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, is an important etiological factor in the development of cardiovascular disease (CVD). Considering the relationship between childhood obesity and CVD risk, it would be worthwhile to evaluate whether previously identified lipid-related variants in adult subjects are associated with lipid variations in a childhood obesity study (n = 482). In an association analysis for 16 genome-wide association study (GWAS)-based candidate loci, we confirmed significant associations of a genetic predisposition to lipoprotein concentrations in a childhood obesity study. Having two loci (rs10503669 at LPL and rs16940212 at LIPC) that showed the strongest association with blood levels of TG and HDL-C, we calculated a genetic risk score (GRS), representing the sum of the risk alleles. It has been observed that increasing GRS is significantly associated with decreased HDL-C (effect size, -1.13 ± 0.07) compared to single nucleotide polymorphism combinations without two risk variants. In addition, a positive correlation was observed between allelic dosage score and risk allele (rs10503669 at LPL) on high TG levels (effect size, 10.89 ± 0.84). These two loci yielded consistent associations in our previous meta-analysis. Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C) overlap to a large extent in childhood as well as in adulthood. Post-GWAS functional characterization of these variants is further required to elucidate their pathophysiological roles and biological mechanisms.
    Genomics & informatics. 06/2012; 10(2):99-105.
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    ABSTRACT: Previous studies have reported a relationship between short sleep duration and childhood overweight. Although school-aged children tend to compensate for weekday sleep deficit by increasing weekend sleep duration, the association between weekend catch-up sleep and childhood overweight remains unclear. This study aimed to examine the relationship between weekend catch-up sleep and being overweight in children. A total of 936 school children (48.2% boys) aged 10 or 11 years participated in this school-based cohort study. Anthropometric measurements including height and body weight were carried out. We obtained data on sleep patterns, lifestyle and parent characteristics using questionnaires. The main outcome measure was childhood overweight. After adjusting for the relevant confounding variables (age, sex, breakfast eating, screen time and parental obesity), longer sleep on weekdays and weekends was associated with decreased odds of childhood overweight (OR: 0.68; 95% CI: 0.54-0.86; OR: 0.64; 95% CI: 0.53-0.77, respectively). Participants with increased catch-up sleep duration during weekends also had decreased odds of being overweight (OR: 0.67; 95% CI: 0.53-0.85). There was an interaction between weekday sleep duration and weekend catch-up sleep in relation to childhood overweight, and this effect of weekend catch-up sleep on being overweight was stronger as the participants slept less on weekdays (P = 0.024). These results indicate that weekend catch-up sleep is independently associated with decreased risk of being overweight in fifth-grade students, and this effect can be varied by the weekday sleep duration. A prospective study is required to confirm this observation.
    Journal of Sleep Research 04/2012; 21(5):546-551. · 3.04 Impact Factor
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    ABSTRACT: Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.
    Biological & Pharmaceutical Bulletin 01/2012; 35(3):369-75. · 1.85 Impact Factor
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    ABSTRACT: Increased adiposity and unhealthy lifestyle augment the risk for type 2 diabetes in children with familial predisposition. Insulin resistance (IR) is an excellent clinical marker for identifying children at high risk for type 2 diabetes. This study was conducted to investigate parental, physiological, behavioral and socio-economic factors related to IR in Korean children. This study is a cross-sectional study using data from 111 children aged 7 years and their parents. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using fasting glucose and insulin level as a marker of IR. All children's adiposity indices (r = 0.309-0.318, all P-value = 0.001) and maternal levels of fasting insulin (r = 0.285, P-value = 0.003) and HOMA-IR (r = 0.290, P-value = 0.002) were positively correlated with children's HOMA-IR level. There was no statistical difference of children's HOMA-IR level according to children's lifestyle habits and socioeconomic status of families. An increase of 1 percentage point in body fat was related to 2.7% increase in children's HOMA-IR (P-value < 0.001) and an increase of 1% of maternal level of HOMA-IR was related to 0.2% increase in children's HOMA-IR (P-value = 0.002). This study shows that children's adiposity and maternal IR are positively associated with children's IR.
    International Journal of Environmental Research and Public Health 12/2011; 8(12):4596-607. · 2.00 Impact Factor
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    ABSTRACT: We investigated the relationship among socioeconomic status factors, the risk of anemia, and iron deficiency among school-aged children in Korea. The sample consisted of fourth-grade students aged 10 y recruited from nine elementary schools in Korean urban areas in 2008 (n = 717). Anthropometric and blood biochemistry data were obtained for this cross-sectional observational study. Anemia was defined as hemoglobin levels lower than 11.5 g/dl. Iron deficiency was defined as serum iron levels lower than 40 ug/dl. We also obtained data on parental education from questionnaires and on children's diets from 3-day food diaries. Parental education was categorized as low or high, with the latter representing an educational level beyond high school. Children with more educated mothers were less likely to develop anemia (P = 0.0324) and iron deficiency (P = 0.0577) than were those with less educated mothers. This group consumed more protein (P = 0.0004) and iron (P = 0.0012) from animal sources than did the children of less educated mothers, as reflected by their greater consumption of meat, poultry, and derivatives (P < 0.0001). Logistic regression analysis revealed a significant inverse relationship between maternal education and the prevalence of anemia (odds ratio: 0.52; 95% confidence interval: 0.32, 0.85). As a contributor to socioeconomic status, maternal education is important in reducing the risk of anemia and iron deficiency and in increasing children's consumption of animal food sources.
    BMC Public Health 11/2011; 11:870. · 2.08 Impact Factor
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    ABSTRACT: The aim of the present study was to identify the major dietary patterns of seven- and eight-year-old Korean children and to examine the relationship between dietary patterns and obesity, nutrient intake, and diet quality. The subjects were 284 seven- and eight-year-old children who participated in the Gwacheon child cohort study. Three dietary patterns emerged from the factor analysis: Korean, modified Western, and Western. Cluster analysis was used to classify the subjects into two dietary groups: Korean and Western diet patterns. The two different dietary patterns were closely related to dietary quality which in turn was related to health risks. The Western diet group had a lower fiber intake, a higher intake of energy, fat and calcium and a higher dietary diversity score (DDS) than the Korean diet group. The number of days when fruit, milk and dairy products were omitted from the diet was higher for the Korean diet group than for the Western group. Dietary patterns and related diet quality should be considered when designing nutrition policy and intervention programs for children.
    Osong public health and research perspectives. 06/2011; 2(1):59-64.
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    ABSTRACT: The low-density lipoprotein receptor (LDLR) plays a central role in cholesterol homeostasis. Here, we provide evidence that an increase in endoplasmic reticulum (ER) stress response or a disturbance of mitochondrial function inhibits LDLR expression in human liver Sk-Hep1 cells. Both organelle stresses triggered activation of activating transcription factor-3 (ATF3), which subsequently reduced LDLR expression. Serial deletion studies revealed that the LDLR promoter region within -234 bp was involved in the repression of LDLR by ATF3. In addition, we identified the region between -8 and -3 of LDLR promoter region as a putative binding site for ATF3 by using deletion construct lacking 6 bp nucleotide corresponding to this region. Transfection of ATF3-specific siRNA rescued LDLR expression under organelle stress, indicating that ATF3 was mainly responsible for the repression of LDLR by these stressors. Additionally, chromatin immunoprecipitation revealed that ATF3 directly binds to the LDLR promoter in a stress-dependent manner. The unique sterol-independent LDLR repression by organelle stress via ATF3 demonstrated here could be involved in obesity-related hypercholesterolemia, which can lead to insulin resistance and type 2 diabetes.
    Biological Chemistry 02/2011; 392(4):377-85. · 2.68 Impact Factor
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    ABSTRACT: Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic β-cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic β-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(ΔC) attenuated ethanol-induced pancreatic β-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers N(γ)-monomethyl-L-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down-regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic β-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and β-cell apoptosis.
    Journal of Biological Chemistry 11/2010; 285(48):37251-62. · 4.65 Impact Factor
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    ABSTRACT: Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic β-cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic β-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(ΔC) attenuated ethanol-induced pancreatic β-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers Nγ-monomethyl-l-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down-regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic β-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and β-cell apoptosis.
    Journal of Biological Chemistry 11/2010; 285(48):37251-37262. · 4.65 Impact Factor
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    ABSTRACT: Associations with FTO (fat mass and obesity associated) gene variants and BMI have been reported in western adult populations. To widen the ethnic and age coverage of the FTO studies, we investigated the effects of FTO gene variants on being overweight and related phenotypes in Korean children and adult with a consideration of lifestyle factors. We genotyped 711 children for 2 FTO SNPs (rs9939973 and rs9939609), analyzed lifestyle factors, and investigated the potential involvement of FTO variants in being overweight comparing with 8842 adults in the KSNP database. With a strong association between FTO gene variants and BMI levels, we further identified an association between rs9939973 or rs9939609 and being overweight both children (P=0.025, OR=1.47, 95% CI=1.05-2.06; P=0.023, OR=1.53, 95% CI=1.06-2.22) and adults (P=0.018, OR=1.10, 95% CI=1.02-1.19; P=0.001, OR=1.16, 95% CI=1.06-1.27). Significant association was observed between rs9939609 and dietary fat intake in children (P=0.008) but not in adults. In low physical activity subgroup of children, rs9939609 A allele carriers had a higher BMI than TT carriers (P=0.0147). A significant interaction effect of rs9939609 on BMI across 3 levels of adult physical activity was found. FTO variant rs9939609 is an overweight susceptibility gene in Koreans. By low physical activity, A allele greatly influenced greater BMI.
    Clinica chimica acta; international journal of clinical chemistry 11/2010; 411(21-22):1716-22. · 2.54 Impact Factor