The potential effects of HECTD4 variants on fasting glucose and triglyceride levels in relation to prevalence of type 2 diabetes based on alcohol intake.

Excessive alcohol intake is an important cause of major public health problem in East Asian countries. Growing evidence suggests that genetic factors are associated with alcohol consumption and the risk for alcohol-associated disease, and these factors contribute to the risk of developing chronic diseases, including diabetes. This study aims to investigate the association of type 2 diabetes with genetic polymorphisms within HECTD4 based on alcohol exposure. We performed a genome-wide association study involving the cohorts of the KoGES-HEXA study (n = 50,028) and Ansan and Ansung study (n = 7,980), both of which are prospective cohort studies in Korea. The top three single-nucleotide polymorphisms (SNPs) of the HECTD4 gene, specifically rs77768175, rs2074356 and rs11066280, were found to be significantly associated with alcohol consumption. We found that individuals carrying the variant allele in these SNPs had lower fasting blood glucose, triglyceride, and GGT levels than those with the wild-type allele. Multiple logistic regression showed that statistically significant associations of HECTD4 gene polymorphisms with an increased risk of type 2 diabetes were found in drinkers. Namely, these SNPs were associated with decreased odds of diabetes in the presence of alcohol consumption. As a result of examining the effect of alcohol on the expression of the HECTD4 gene, ethanol increased the expression of HECTD4 in cells, but the level was decreased by NAC treatment. Similar results were obtained from liver samples of mice treated with alcohol. Moreover, a loss of HECTD4 resulted in reduced levels of CYP2E1 and lipogenic gene expression in ethanol-treated cells, while the level of ALDH2 expression increased, indicating a reduction in ethanol-induced hepatotoxicity.

Down-regulation of the mitochondrial i-AAA protease Yme1L induces muscle atrophy via FoxO3a and myostatin activation.

Muscle atrophy is closely associated with many diseases, including diabetes and cardiac failure. Growing evidence has shown that mitochondrial dysfunction is related to muscle atrophy; however, the underlying mechanisms are still unclear. To elucidate how mitochondrial dysfunction causes muscle atrophy, we used hindlimb-immobilized mice. Mitochondrial function is optimized by balancing mitochondrial dynamics, and we observed that this balance shifted towards mitochondrial fission and that MuRF1 and atrogin-1 expression levels were elevated in these mice. We also found that the expression of yeast mitochondrial escape 1-like ATPase (Yme1L), a mitochondrial AAA protease was significantly reduced both in hindlimb-immobilized mice and carbonyl cyanide m-chlorophenylhydrazone (CCCP)-treated C2C12 myotubes. When Yme1L was depleted in myotubes, the short form of optic atrophy 1 (Opa1) accumulated, leading to mitochondrial fragmentation. Moreover, a loss of Yme1L, but not of LonP1, activated AMPK and FoxO3a and concomitantly increased MuRF1 in C2C12 myotubes. Intriguingly, the expression of myostatin, a myokine responsible for muscle protein degradation, was significantly increased by the transient knock-down of Yme1L. Taken together, our results suggest that a deficiency in Yme1L and the consequential imbalance in mitochondrial dynamics result in the activation of FoxO3a and myostatin, which contribute to the pathological state of muscle atrophy.

Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with ß-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. METHODS: Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. RESULTS: ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. CONCLUSIONS: Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. LAY SUMMARY: Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.

Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity.

Adipogenesis, the conversion of precursor cells into adipocytes, is associated with obesity and is mediated by glucocorticoids acting via hitherto poorly characterized mechanisms. Dexras1 is a small G protein of the Ras family discovered on the basis of its marked induction by the synthetic glucocorticoid dexamethasone. We show that Dexras1 mediates adipogenesis and diet-induced obesity. Adipogenic differentiation of 3T3-L1 cells is abolished with Dexras1 depletion, whereas overexpression of Dexras1 elicits adipogenesis. Adipogenesis is markedly reduced in mouse embryonic fibroblasts from Dexras1-deleted mice, whereas adiposity and diet-induced weight gain are diminished in the mutant mice.

Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.

Chronic ethanol consumption induces pancreatic ß-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic ß-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 to -158 bp) on the Gck promoter were up-regulated. 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. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and ß-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters ß-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis.

Regulation of retinoid X receptor gamma expression by fed state in mouse liver.

Glucose metabolism is balanced by glycolysis and gluconeogenesis with precise control in the liver. The expression of genes related to glucose metabolism is regulated primarily by glucose and insulin at transcriptional level. Nuclear receptors play important roles in regulating the gene expression of glucose metabolism at transcriptional level. Some of these nuclear receptors form heterodimers with RXRs to bind to their specific regulatory elements on the target promoters. To date, three isotypes of RXRs have been identified; RXRα, RXRß and RXRγ. However, their involvement in the interactions with other nuclear receptors in the liver remains unclear. In this study, we found RXRγ is rapidly induced after feeding in the mouse liver, indicating a potential role of RXRγ in controlling glucose or lipid metabolism in the fasting-feeding cycle. In addition, RXRγ expression was upregulated by glucose in primary hepatocytes. This implies that glucose metabolism governed by RXRγ in conjunction with other nuclear receptors. The luciferase reporter assay showed that RXRγ as well as RXRα increased SREBP-1c promoter activity in hepatocytes. These results suggest that RXRγ may play an important role in tight control of glucose metabolism in the fasting-feeding cycle.

Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation.

Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor γ (PPARγ), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARγ overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARγ by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARγ overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARγ, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans.

Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis.

Recently, hepatic peroxisome proliferator-activated receptor (PPAR)γ has been implicated in hepatic lipid accumulation. We found that the C3H mouse strain does not express PPARγ in the liver and, when subject to a high-fat diet, is resistant to hepatic steatosis, compared with C57BL/6 (B6) mice. Adenoviral PPARγ2 injection into B6 and C3H mice caused hepatic steatosis, and microarray analysis demonstrated that hepatic PPARγ2 expression is associated with genes involved in fatty acid transport and the triglyceride synthesis pathway. In particular, hepatic PPARγ2 expression significantly increased the expression of monoacylglycerol O-acyltransferase 1 (MGAT1). Promoter analysis by luciferase assay and electrophoretic mobility shift assay as well as chromatin immunoprecipitation assay revealed that PPARγ2 directly regulates the MGAT1 promoter activity. The MGAT1 overexpression in cultured hepatocytes enhanced triglyceride synthesis without an increase of PPARγ expression. Importantly, knockdown of MGAT1 in the liver significantly reduced hepatic steatosis in 12-wk-old high-fat-fed mice as well as ob/ob mice, accompanied by weight loss and improved glucose tolerance. These results suggest that the MGAT1 pathway induced by hepatic PPARγ is critically important in the development of hepatic steatosis during diet-induced obesity.

Transcription factor Snail is a novel regulator of adipocyte differentiation via inhibiting the expression of peroxisome proliferator-activated receptor γ.

Snail belongs to the superfamily of zinc-finger transcription factors and plays a crucial role in processes regulating cell fate, such as the formation of mesoderm and initiation of epithelial-mesenchymal transition. We have previously discovered that Snail modulates adiponectin expression in 3T3-L1 cells during adipogenesis. In the present study, we elucidated the functional role of Snail in adipocyte differentiation and its underlying molecular mechanism. Snail expression was dramatically decreased during adipogenesis in 3T3-L1 cells. Overexpression of Snail blocked adipocyte differentiation by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha, while knockdown of Snail expression stimulated adipogenesis in 3T3-L1 cells. Chromatin immunoprecipitation assay and luciferase assay showed that Snail inhibits the transcriptional activity of the PPARγ gene by directly binding to the E-box motifs in the PPARγ promoter. Wnt10b induced phosphorylation of glycogen synthase kinase 3 beta (GSK3ß), leading to inhibition of adipogenesis in 3T3-L1 cells in accordance with increased expression of Snail, whereas adipogenic capacity was restored in Snail siRNA-transfected preadipocytes. LiCl (a GSK3ß inhibitor)-treated cells also showed increased expression of Snail, with a reduced adipogenic potential. Snail-overexpressing 3T3-F442A cells did not differentiate into mature adipocytes in immunodeficient nude mice. Taken together, Snail is a novel regulator of adipocyte differentiation, which acts by direct suppression of PPARγ expression. Our data also indicate that the expression of Snail is mediated by the Wnt-GSK3ß signaling pathway.

Association between neck circumference and pulmonary function in Korean adults.

Neck circumference (NC) is associated with various diseases. However, its association with pulmonary diseases remains unclear. This study aimed to investigate the association between NC and pulmonary function in Korean adults. Data from the 2019 Korean National Health and Nutrition Examination Survey were used, including forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). A total of 3818 adults aged 40 to 79 years were included in the analysis. Multivariable logistic regression models were used to examine factors associated with low pulmonary function (<80% of the predicted value) and calculate odds ratios (ORs) and 95% confidence intervals (CIs) for decreased lung function per 1-cm increase in NC. A negative correlation was observed between the NC and pulmonary function in both sexes. In multivariate logistic regression analyses, in contrast to men, women exhibited a notable relationship between increased NC and impaired pulmonary function, with a more pronounced effect observed in FVC (OR, 1.14; 95% CI, 1.05-1.24). Central obesity may play a role in pulmonary function decline. Understanding this relationship can inform preventive strategies and interventions to improve the respiratory health of individuals with central obesity.

Acute Emotional Impact of Peer Suicide and Student-Related Factors.

OBJECTIVE: This study explored the negative emotional impact of peer suicide on adolescent students during the early stages of becoming aware of suicide and examined the adverse effects of related environmental and mental health factors. METHODS: This study was conducted from March 1, 2020 to December 31, 2021, targeting students enrolled in middle and high schools where student suicide occurred. Emotional impact was assessed using the Korean version of the Impact of Event Scale-Revised (IES-R-K), State-Trait Anxiety Inventory-X, Center for Epidemiologic Studies-Depression Scale (CES-D), and Beck's Scale for Suicide Ideation (SSI). χ2 test and Pearson's correlation analysis were performed to analyze subgroup differences and explore relationships between scale scores, respectively. RESULTS: Of the 2,382 participants, 25.1% belonged to the post-traumatic stress disorder (PTSD) or PTSD tendency group on the IES-R-K, and 22.2% showed abnormalities in the State-Trait Anxiety Inventory-State. Students in the same class as the deceased student and those in the same grade but in different classes had higher risk rates than those in different grades. Boarding school students had 1.9 times higher odds of experiencing emotional impacts than non-boarding students. On the CES-D, 10.4% of the students showed potential depression, with 3.7 times higher odds of experiencing emotional impact than those with normal scores. Moreover, 4.5% of the students reported suicidal ideation on the SSI, with those experiencing mild suicidal ideation having 1.9 times higher odds of experiencing emotional impact than those with normal scores. CONCLUSION: A significant proportion of students experienced negative impacts of peer suicide. Students in close-knit environments, such as the same class, grade, and boarding school as the deceased, or those with depression or anxiety experienced a more pronounced negative impact.

Vitamin D ameliorates age-induced nonalcoholic fatty liver disease by increasing the mitochondrial contact site and cristae organizing system (MICOS) 60 level.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Despite intensive research, considerable information on NAFLD development remains elusive. In this study, we examined the effects of vitamin D on age-induced NAFLD, especially in connection with mitochondrial abnormalities. We observed the prevention of NAFLD in 22-month-old C57BL/6 mice fed a vitamin D3-supplemented (20,000 IU/kg) diet compared with mice fed a control (1000 IU/kg) diet. We evaluated whether vitamin D3 supplementation enhanced mitochondrial functions. We found that the level of mitochondrial contact site and cristae organizing system (MICOS) 60 (Mic60) level was reduced in aged mice, and this reduction was specifically restored by vitamin D3. In addition, depletion of Immt, the human gene encoding the Mic60 protein, induced changes in gene expression patterns that led to fat accumulation in both HepG2 and primary hepatocytes, and these alterations were effectively prevented by vitamin D3. In addition, silencing of the vitamin D receptor (VDR) decreased the Mic60 levels, which were recovered by vitamin D treatment. To assess whether VDR directly regulates Mic60 levels, we performed chromatin immunoprecipitation and reporter gene analysis. We discovered that VDR directly binds to the Immt 5' promoter region spanning positions -3157 to -2323 and thereby upregulates Mic60. Our study provides the first demonstration that a reduction in Mic60 levels due to aging may be one of the mechanisms underlying the development of aging-associated NAFLD. In addition, vitamin D3 could positively regulate Mic60 expression, and this may be one of the important mechanisms by which vitamin D could ameliorate age-induced NAFLD.

The association between oxidative balance score and lung function: A nationwide cross-sectional survey.

Purpose: Given the impact of oxidative imbalance on the development of airway pathologies, this study was undertaken to investigate the association between oxidative balance (OB) scores and lung function in the adult Korean population. Methods: Data of 17,368 adults with available OB scores and pulmonary function test results were extracted from the 2013-2019 Korean National Health and Nutrition Examination Surveys. Multivariable logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for reduced forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) per 1-point decrease in OB score. Dose dependent association of reduced lung function with OB scores was also investigated. Results: Males, low-income subjects, individuals with comorbidities, and those with reduced pulmonary function had lower OB scores (representing oxidative balance). Overall, the association between oxidative imbalance and reduced lung function was remarkable in FVC than FEV1 (OR [95% CI], 1.06 [1.04-1.07] vs. 1.03 [1.02-1.04]; both p < 0.001). Linear relationships between the level of reduced lung function and OB scores were significantly noted (p for trend<0.001 in both FEV1 and FVC). Conclusion: Our findings suggest that oxidative imbalance is associated with reduced pulmonary function.

Low Serum Creatinine as Well as High Serum Creatinine Is Associated with Prognosis of Patients with Cancer in End-of-Life.

Background: The prognosis of end-of-life patients is challenging, and clinicians have attempted to predict survival more accurately. High serum creatinine (sCr) levels are associated with lower survival rates in patients with various cancers; however, low sCr levels are commonly expected in patients with terminal cancer because of muscle wasting and malnutrition. Therefore, we investigated the prevalence of low and high sCr levels and their association with survival duration in patients with terminal cancer in a palliative care unit. Methods: We analyzed the medical records of 280 patients admitted to a palliative care unit. Patients were divided into low (<0.5 mg/dL), normal (0.5-1.2 mg/dL), and high (>1.2 mg/dL) sCr groups. Kaplan-Meier survival curves using sCr levels were plotted and compared using the log-rank test. Using stepwise selection, a multivariable Cox proportional hazards model was used to identify the significant prognostic factors. Results: The median survival durations in the high-, low-, and normal-sCr groups were 9.57 days, 22.26 days, and 27.51 days, respectively. Multivariable Cox proportional hazard model identified that males (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.16-2.85), poor performance status (HR, 3.43; 95% CI, 1.12-10.54), total parenteral nutrition use (HR, 1.84; 95% CI, 1.09-3.1), high sCr (HR, 2.74; 95% CI, 1.52-4.94), and low sCr (HR, 1.22; 95% CI, 1.07-1.43) were significantly associated with a shorter survival time. Conclusion: Low and high serum creatinine levels were significantly associated with poor survival in patients with cancer at the end-of-life stage. Therefore, readily available and simple biomarkers may help plan advanced care in palliative care settings.

Association Between Oral Health Status and Survival Time in Terminally Ill Cancer Patients.

INTRODUCTION: Patients with terminal cancer often experience various oral problems. Whether oral health status is associated with the survival of terminally ill cancer patients receiving palliative care remains unclear. METHODS: We analyzed the data of 59 Korean patients with terminal cancer receiving palliative care, including their oral health status, using a modified Korean version of the Oral Health Assessment Tool (OHAT). Patients were categorized into "Good," "Moderate," or "Poor" groups based on OHAT scores. The Kaplan-Meier method was used to compare the median survival time, and the prognosis between groups was estimated using Cox proportional hazard models. RESULTS: The most common oral symptoms observed were xerostomia (69.5%) and mucositis (17.0%). Significantly shorter survival times were observed in patients with hyperbilirubinemia, elevated creatinine levels, and no use of dentures. The "Poor" group had a shorter survival than the "Good" oral group (P = .010). A multivariate Cox proportional hazards analysis revealed that the "Poor" group was significantly associated with poor survival compared to the "Good" group (hazard ratio, 2.05; P = .047). CONCLUSION: Terminally ill cancer patients with poor oral health may have a higher risk of shorter survival. Palliative care professionals should pay attention to oral health. Further research is needed to determine the effects of oral care on survival.

Associations between local acidosis induced by renal LDHA and renal fibrosis and mitochondrial abnormalities in patients with diabetic kidney disease.

During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms' tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD.

Targeting of a developmentally regulated epitope of CD43 for the treatment of acute leukemia.

Previously, we developed a JL1 mouse monoclonal antibody that specifically recognizes the leukemic cells of T, B, and myeloid lineages, but not the peripheral blood cells and pluripotent hematopoietic stem cells. Here, we identified that JL1 mAb recognized a specific epitope of human CD43 and validated its potential as an anti-leukemic targeting agent. After the comprehensive screening of JL1 Ag in the human thymocyte cDNA library, multiple fusion gene constructs encoding human CD43 were generated to identify its specific epitope to JL1 antibody. JL1 antibody interacted with a developmentally regulated and non-glycosylated epitope of the human CD43 extracellular domain (AA 73-81, EGSPLWTSI). In an in vivo leukemia model using NOD/SCID mice injected with CCRF-CEM7 cells, JL1 antibody induced effective cytotoxicity in tumor cells and prolonged survival (p < 0.05). Saporin conjugation to JL1 antibody effectively depleted tumor cells in in vitro cytotoxic assays and also prolonged survival in a leukemic mouse model (p < 0.001). These preclinical results further support the therapeutic potential of the JL1 antibody in the management of acute leukemia.

Vitamin D Rescues Pancreatic ß Cell Dysfunction due to Iron Overload via Elevation of the Vitamin D Receptor and Maintenance of Ca2+ Homeostasis.

SCOPE: Accumulating evidence indicates that micronutrients are related to metabolic diseases. However, comparatively less attention has been devoted to their influence on each other during the development of metabolic diseases. To investigate the underlying mechanisms, the effects of iron and vitamin D on pancreatic ß cell functions are examined. METHODS AND RESULTS: Iron overload is induced in INS-1 rat insulinoma pancreatic ß cells and it is found that iron overload dramatically reduce expression of the vitamin D receptor (VDR). Iron overload-induced ß cell dysfunction is rescued by 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) cotreatment via restoration of VDR level and the consequent maintenance of Ca2+ homeostasis. Iron accumulation is also observed in the islets of 22-month-old C57BL/6 mice fed with a chow diet (1000 IU vitamin D3 per kg). In contrast, islet iron accumulation and hyperinsulinemia are ameliorated in mice fed with a vitamin D3 -supplemented diet (20 000 IU kg-1 ). CONCLUSION: The authors show that functional failure of ß cells due to iron accumulation is rescued by 1,25(OH)2 D3 , and iron overload significantly reduces VDR levels in ß cells. These results suggest that iron and vitamin D inversely influence pancreatic ß cell function.

Association between the incidence of hypertension and alcohol consumption pattern and the alcohol flushing response: A 12-year follow-up study.

BACKGROUND: Alcohol consumption is associated with hypertension, and this association depends on the alcohol consumption pattern and alcohol flushing response. In this 12-year follow-up study, we investigated the relationship between the alcohol consumption pattern and incidence of hypertension in the Korean population. METHODS: We analyzed 1,366 Korean participants in the Ansung-Ansan cohort study without hypertension at baseline. The subjects were classified into four alcohol consumption patterns: never-drinking, light alcohol consumption, moderate alcohol consumption, and heavy alcohol consumption, and as flushers or non-flushers in response to alcohol. RESULTS: In flushers, moderate and heavy alcohol consumption patterns increased the risk of incident hypertension compared with never-drinkers [moderate: HR 1.811 (95% CI 1.084-3.028); heavy: HR 2.494 (95% CI 1.185-5.247)], but non-flushers were not associated with increased risk of incident hypertension according to the alcohol consumption pattern. In addition, a heavy alcohol consumption pattern increased the risk of hypertension among flushers compared with non-flushers [HR 2.232 (95% CI 1.054-4.728)]. CONCLUSION: In this 12-year follow-up study, we observed that moderate and heavy alcohol consumption was associated with an increased risk of hypertension in flushers. Especially, a heavy alcohol consumption pattern in flushers markedly increased the risk of hypertension.

Alcohol consumption before pregnancy causes detrimental fetal development and maternal metabolic disorders.

Alcohol consumption before or during pregnancy poses serious health risks to the fetus; however, the underlying mechanisms involved remain obscure. Here, we investigated whether ethanol consumption before pregnancy affects maternal or fetal health and whether pharmacological inhibition of CYP2E1, a major ethanol oxidation enzyme, by 4-methylpyrazole (4-MP) has therapeutic effects. We found that ethanol consumption (5%) 2 weeks before pregnancy resulted in a decrease in the number of viable fetuses and abnormal fetal development, and these effects were accompanied by impaired maternal glucose homeostasis and hepatic steatosis during pregnancy. Neonates of ethanol-fed mice had postnatal macrosomia and significantly decreased growth rates during the lactation period. However, treatment with 4-MP, a CYP2E1 inhibitor, markedly ameliorated the reduction in insulin action and glucose disposal responsiveness in the livers of ethanol-fed mice. Blockage of CYP2E1 significantly reduced the alteration in hepatic lipid deposition, fatty acid oxidation, mitochondrial energy status, and macrophage infiltration observed in ethanol-fed mice. Finally, there was a positive correlation between postnatal macrosomia or growth retardation and increased inflammatory responses. Collectively, our study suggests that even moderate ethanol intake may be detrimental to fetal development and may cause growth retardation through maternal metabolic disorders.