Hyangkyu Lee

Nonmuscle myosin II localization is regulated by JNK during Drosophila larval wound healing

We investigated cell shape changes during wound closure in the Drosophila larval epidermis. During reepithelialization, epidermal cells permanently change shape from pentagonal or hexagonal to irregular forms. This process requires zipper, a gene encoding the Drosophila nonmuscle myosin II heavy chain. Following wounding, myosin II is localized at the wound margin and at the rear end of individual cells located within several rows from the wound hole. The c-Jun N-terminal kinase (JNK) pathway is essential for this myosin II localization. These results suggest that not only the wound leading edge but also the cells lying distal to the leading edge cells actively participate in epithelial cell sheet migration during wound hole closure.

Rho-family small GTPases are required for cell polarization and directional sensing in Drosophila wound healing.

A wound induces cell polarization, in which myosin II is localized at the rear end of individual cells in a migrating epithelial sheet of the Drosophila larval epidermis. Here, we use myosin localization to demonstrate that Rac1, Cdc42, and Rho1 are each required for cell polarization and directional sensing of the wound. The three GTPases are also required for actin cable formation at the wound leading edge. Rac1, Cdc42, and Rho1 act upstream of c-Jun N-terminal kinase (JNK) to organize actin assembly. These results highlight the similarities between the molecular mechanism of Drosophila wound healing and those of Drosophila embryonic dorsal closure and the chemotactic response of Dictyostelium and leukocytes.

Requirement for Pak3 in Rac1-induced organization of actin and myosin during Drosophila larval wound healing

Rho‐family small GTPases regulate epithelial cell sheet migration by organizing actin and myosin during wound healing. Here, we report that Pak3, but not Pak1, is a downstream target protein for Rac1 in wound closure of the Drosophila larval epidermis. Pak3‐deficient larvae failed to close a wound hole and this defect was not rescued by Pak1 expression, indicating differential functions of the two proteins. Pak3 localized to the wound margin, which selectively required Rac1. Pak3‐deficient larvae showed severe defects in actin‐myosin organization at the wound margin and in submarginal cells, which was reminiscent of the phenotypes of Rac1‐deficient larvae. These results suggest that Pak3 specifically mediates Rac1 signaling in organizing actin and myosin during Drosophila epidermal wound healing.

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.

Serum carcinoembryonic antigen is associated with abdominal visceral fat accumulation in female Korean nonsmokers.

Background Carcinoembryonic antigen (CEA) is a tumor marker overexpressed in adenocarcinoma that has proinflammatory properties. Recent studies have reported that CEA is positively associated with carotid atherosclerosis and metabolic syndrome. Because visceral obesity is a known risk factor for cardiometabolic diseases, CEA may also be associated with visceral adiposity. Therefore, we investigated the relationship between serum CEA concentration and visceral obesity in female Korean nonsmokers. Methods A total of 270 Korean female nonsmokers were enrolled during their routine health check-ups. Biomarkers of metabolic risk factors were assessed along with body composition by computed tomography. Serum CEA levels were measured by using a chemiluminescence immunoassay analyzer. Results Serum CEA levels correlated with visceral fat area, fasting glucose, and triglyceride levels after adjusting for age and BMI. The mean visceral fat area increased significantly with the increasing CEA tirtiles. In a step-wise multiple regression analysis, age (β = 0.26, p<0.01) and visceral fat area (β = 0.19, p = 0.03) were identified as explanatory variables for serum CEA level. Conclusions This study suggested that CEA may be a mediator that links metabolic disturbance and tumorigenesis in visceral obesity. Further studies are required to better understand the clinical and pathophysiological significance of our findings.

Relationship between non-alcoholic fatty liver disease, metabolic syndrome and insulin resistance in Korean adults: A cross-sectional study.

BACKGROUND We investigated the independent and combined impact of obesity and nonalcoholic fatty liver disease (NAFLD) on components and prevalence of metabolic syndrome in Korean adults. METHODS This study included 1695 adults (500 males and 1,195 females), who took part in a regular health check-up at the community-based health promotion center. Participants were divided according to degree of adiposity and the presence of NAFLD. The components and prevalence of metabolic syndrome were compared. RESULTS Fasting glucose was significantly higher in nonobese participants with NAFLD compared to obese participants without NAFLD. Logistic regression analysis revealed that the presence of NAFLD was associated with 3.63 times increased prevalence of metabolic syndrome (95% CI: 1.21-10.86) while obesity without NAFLD was associated with 3.84 times increased prevalence of metabolic syndrome (95% CI: 1.57-9.36) in male. In female, the presence of NAFLD was associated with 5.56 times higher prevalence of metabolic syndrome (95% CI: 2.53-12.23) while obesity without NAFLD had 3.46 times increased prevalence of metabolic syndrome (95% CI: 1.64-7.33). CONCLUSIONS NAFLD is associated with the prevalence of metabolic syndrome, independent of adiposity. In females, NAFLD may be a more important factor than obesity for risk of metabolic syndrome.

The regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase by autophagy in low-glycolytic hepatocellular carcinoma cells

The glycolytic phenotype is a dominant metabolic phenomenon in cancer and is reflected in becoming aggressive. Certain hepatocellular carcinoma lack increased glycolysis and prefer to uptake acetate than glucose for metabolism. Autophagy plays a role in preserving energies and nutrients when there is limited external nutrient supply and maintains glucose level of blood though supporting gluconeogenesis in the liver. As the role of autophagy and gluconeogenesis in HCC following the glycolic activity was not clear, we cultured HCC cells with different glycolytic levels in Hanks balanced salt solution (HBSS) to induce autophagy and conducted the activity of gluconeogenesis. Both autophagy and gluconeogenesis were induced in low glycolytic HCC cells (HepG2). In glycolytic Hep3B cells, only autophagy without gluconeogenesis was induced upon starvation. When autophagy was blocked, the level of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was reduced in HepG2 cells and not in Hep3B. Altogether, we investigated contribution of hepatic gluconeogenesis to the metabolic phenotype of HCC cells and the role of autophagy as a potential mechanism regulating gluconeogenesis in low glycolytic HCC.

Predominance of small dense LDL differentiates metabolically unhealthy from metabolically healthy overweight adults in Korea

OBJECTIVE The purposes of this study were (1) to determine the association between lipoprotein subfraction profiles and metabolically healthy overweight (MHO) phenotype, as defined by visceral adiposity; and (2) to identify the strongest predictor of metabolic health among the lipoprotein measurements. MATERIALS/METHODS This cross-sectional study was comprised of 462 overweight patients, who were classified as MHO or non-MHO based on their visceral adipose tissue (VAT) area to subcutaneous adipose tissue area (SAT) ratio (VAT/SAT ratio). Serum lipoprotein subfraction analyses and other metabolic parameters were measured. RESULTS Among the overweight participants, two hundred fifty-five individuals (53.7%) had the MHO phenotype. After adjusting for age, sex, medication, lifestyle factors, and confounding metabolic characteristics, the non-MHO group showed significantly higher lipid levels and a greater prevalence of unfavorable lipid profiles. LDL subclass pattern type B was the most significant predictor of the non-MHO phenotype (odds ratio 2.70; 95% CI 1.55-4.69), while serum LDL cholesterol level was not a significant predictor of the non-MHO phenotype. CONCLUSIONS Lipoprotein subfraction particle measurements were significantly associated with the non-MHO phenotype and a higher VAT/SAT ratio, with small dense LDL predominance being the most significant predictor of MHO phenotype. These findings will help identify MHO and non-MHO phenotypes and perhaps lead to a development of cost-effective individualized treatments.

Effects of an Integrated Stress Management Program (ISMP) for Psychologically Distressed Students: A Randomized Controlled Trial

PURPOSE This study aimed to evaluate the effects of an integrated stress management program (ISMP) on college life stress, stress coping, psychological distress, and cortisol among male college students. DESIGN AND METHODS Out of 137 initially enrolled students, 99 participants were identified as distressed subjects and randomly assigned to either the ISMP or control group. Ultimately, 84 participants (43: experimental, 41: control) completed pretest-posttest. The experimental group received eight 2-hr sessions over 4 weeks. FINDINGS Stress and psychological distress decreased significantly, whereas stress coping and cortisol did not improve significantly. PRACTICE IMPLICATIONS Further studies with longer follow-up periods and physiological interventions are required.

Comparing kidney outcomes in type 2 diabetes treated with different sulphonylureas in real-life clinical practice

AIM Although several sulphonylureas are widely used in type 2 diabetes (T2D), their differential impacts on long-term major kidney outcomes remain unclear. This study aimed to investigate the effects of the two most commonly prescribed sulphonylureas, glimepiride and gliclazide, on kidney outcomes in patients with T2D. METHODS A total of 4486 patients treated with either glimepiride or gliclazide for more than 2 years were followed for up to 5.5 years (median: 4.7 years). A propensity score based on baseline characteristics was used to match 1427 patients treated with glimepiride with 1427 gliclazide-treated patients; incidences of end-stage renal disease (ESRD) and sustained doubling of creatinine to>132.6 μmol/L (1.5mg/dL) were also compared. RESULTS In the matched cohort with 12,122 person-years of follow-up, there was no significant difference between groups in risk of ESRD [hazard ratio (HR): 0.57, 95% confidence interval (CI): 0.29-1.12] or doubling of creatinine (HR: 0.74, 95% CI: 0.44-1.26), although there was a trend towards higher risks in the glimepiride group. Subgroup analyses showed that, compared with glimepiride, gliclazide was associated with a lower risk of doubling of creatinine in patients with preserved renal function (glomerular filtration rate ≥ 60 mL/min/1.73 m(2), HR: 0.21, 95% CI: 0.04-0.99) and good glycaemic control (HbA1c < 7%, HR: 0.35, 95% CI: 0.14-0.86), and in older subjects (≥ 62 years, HR: 0.52, 95% CI: 0.27-0.99). CONCLUSION In a real-life setting, there was no significant difference in clinical outcomes of kidney disease for patients treated with glimepiride vs gliclazide. However, gliclazide appeared to protect against renal complication progression in certain populations.