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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.
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Pueblo Asiatico , Obesidad Abdominal , Adulto , Femenino , Humanos , Masculino , Pulmón , Encuestas Nutricionales , República de Corea/epidemiología , Persona de Mediana Edad , Anciano , Pueblos del Este de AsiaRESUMEN
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.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Animales , Ratones , Lactante , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Vitamina D/farmacología , Vitamina D/uso terapéutico , Vitamina D/metabolismo , Membranas Asociadas a Mitocondrias , Ratones Endogámicos C57BL , Membranas Mitocondriales/metabolismoRESUMEN
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.
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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.
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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.
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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.
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Acidosis , Diabetes Mellitus , Nefropatías Diabéticas , Acidosis/complicaciones , Animales , Nefropatías Diabéticas/metabolismo , Fibrosis , Humanos , Lactato Deshidrogenasa 5 , Lactatos/uso terapéutico , Ratas , Estreptozocina/uso terapéutico , Proteínas WT1/uso terapéuticoRESUMEN
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.
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Diabetes Mellitus Tipo 2 , Consumo de Bebidas Alcohólicas/efectos adversos , Aldehído Deshidrogenasa Mitocondrial/genética , Animales , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Etanol , Ayuno , Estudio de Asociación del Genoma Completo , Glucosa , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Prevalencia , Estudios Prospectivos , Triglicéridos , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
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.
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Calcio/metabolismo , Colecalciferol/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Sobrecarga de Hierro/patología , Receptores de Calcitriol/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Línea Celular , Homeostasis/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Hierro/metabolismo , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratas , Vitamina D/análogos & derivados , Vitamina D/farmacologíaRESUMEN
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.
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Consumo de Bebidas Alcohólicas , Rubor/inducido químicamente , Hipertensión , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Hipertensión/epidemiología , Incidencia , República de Corea , Factores de RiesgoRESUMEN
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.
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Consumo de Bebidas Alcohólicas/efectos adversos , Inhibidores del Citocromo P-450 CYP2E1/administración & dosificación , Macrosomía Fetal/tratamiento farmacológico , Glucosa/metabolismo , Complicaciones del Embarazo/tratamiento farmacológico , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Animales , Animales Recién Nacidos , Inhibidores del Citocromo P-450 CYP2E1/farmacología , Modelos Animales de Enfermedad , Hígado Graso/inducido químicamente , Femenino , Desarrollo Fetal/efectos de los fármacos , Macrosomía Fetal/inducido químicamente , Homeostasis/efectos de los fármacos , Ratones , EmbarazoRESUMEN
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.
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Proteína Forkhead Box O3/metabolismo , Metaloendopeptidasas/antagonistas & inhibidores , Mitocondrias/patología , Proteínas Mitocondriales/antagonistas & inhibidores , Atrofia Muscular/patología , Miostatina/metabolismo , Animales , Regulación hacia Abajo , Proteína Forkhead Box O3/genética , Masculino , Metaloendopeptidasas/genética , Metaloendopeptidasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Miostatina/genéticaRESUMEN
BACKGROUND: Excessive alcohol consumption is a major public health problem in East Asian countries. Alcohol use leads to a cascade of problems including increased chances of risky behavior and a wide range of negative health consequences, from alcoholic liver disease to upper gastric and liver cancer. These alcohol effects are known to be influenced by ethnic variability and genetics. METHODS: In this study, subjects were administered a single dose of alcohol (0.6 g/kg for men or 0.4 g/kg for women), and blood alcohol and acetaldehyde concentrations were measured eight times over 5 hours. To investigate genetically susceptible factors to alcohol metabolism, we selected single-nucleotide polymorphisms (SNP) of genes identified by prior genetic association studies for alcohol metabolism, alcohol consumption, alcohol dependence, and related traits, and performed genotyping on all subjects (n = 104). RESULTS: We identified variations in the ADH1A, SRPRB, and PGM1 genes, which are directly associated with blood alcohol or acetaldehyde concentrations. Namely, the T allele of SRPRB rs17376019 and the C allele of PGM1 rs4643 were associated with lower blood alcohol levels, while the ADH1 rs1229976 C allele group exhibited markedly higher blood acetaldehyde levels than those of the ADH1 rs1229976 T allele group. CONCLUSION: This study demonstrates that genetic variations in ADH1A, SRPRB, and PGM1 are associated with variations in blood alcohol and acetaldehyde concentration after alcohol intake.
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Alcohol Deshidrogenasa/genética , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Proteínas de Unión al GTP/genética , Fosfoglucomutasa/genética , Proteínas Proto-Oncogénicas/genética , Acetaldehído/sangre , Adulto , Alelos , Nivel de Alcohol en Sangre , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , República de Corea/etnologíaRESUMEN
Mesenchymal stem cells have the capacity to give rise to multiple cell types, such as adipocytes, osteoblasts, chondrocytes, and myocytes. However, the molecular events responsible for the lineage specification and differentiation of mesenchymal stem cells remain unclear. Using gene expression profile studies, we determined that Scavenger receptor class A, member 5 (SCARA5) is a novel mediator of adipocyte commitment. SCARA5 was expressed at a higher level in committed A33 preadipocyte cells compared to C3H10T1/2 pluripotent stem cells. Gain- and loss-of-function studies likewise revealed that SCARA5 acts as a mediator of adipocyte commitment and differentiation in both A33 and C3H10T1/2 cells. RNAi-mediated knockdown of SCARA5 in A33 cells markedly inhibited the adipogenic potential, whereas overexpression of SCARA5 enhanced adipocyte differentiation in C3H10T1/2 cells. We also demonstrated that the focal adhesion kinase (FAK) and ERK signaling pathways is associated with the SCARA5-mediated response, thereby modulating adipocyte lineage commitment and adipocyte differentiation. Additionally, glucocorticoids induced the expression of SCARA5 in differentiating adipocytes through glucocorticoids response elements (GRE) in the SCARA5 promoter. Taken together, our study demonstrates that SCARA5 is a positive regulator in adipocyte lineage commitment and early adipogenesis in mesenchymal stem cells.
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Adipogénesis , Regulación del Desarrollo de la Expresión Génica , Células Madre Mesenquimatosas/citología , Receptores Depuradores de Clase A/genética , Adipocitos/citología , Adipocitos/metabolismo , Animales , Línea Celular , Células Madre Mesenquimatosas/metabolismo , Ratones , Regiones Promotoras Genéticas , Receptores Depuradores de Clase A/metabolismo , Regulación hacia ArribaRESUMEN
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.
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Factor de Transcripción Activador 3/metabolismo , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factor de Transcripción Activador 3/antagonistas & inhibidores , Factor de Transcripción Activador 3/genética , Adulto , Anciano , Animales , Biomarcadores/metabolismo , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Resistencia a la Insulina , Hígado/metabolismo , Hígado/patología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo , Estudios Prospectivos , ARN Interferente Pequeño/genética , Ratas , Ratas Zucker , Regulación hacia ArribaRESUMEN
Monoacylglycerol acyltransferase 1 (MGAT) is a microsomal enzyme that catalyzes the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG). However, the subcellular localization and catalytic function domain of this enzyme is poorly understood. In this report, we identified that murine MGAT1 localizes to the endoplasmic reticulum (ER) under normal conditions, whereas MGAT1 co-localize to the lipid droplets (LD) under conditions of enriching fatty acids, contributing to TAG synthesis and LD expansion. For the enzyme activity, both the N-terminal transmembrane domain and catalytic HPHG motif are required. We also show that the transmembrane domain of MGAT1 consists of two hydrophobic regions in the N-terminus, and the consensus sequence FLXLXXXn, a putative neutral lipid-binding domain, exists in the first transmembrane domain. Finally, MGAT1 interacts with DGAT2, which serves to synergistically increase the TAG biosynthesis and LD expansion, leading to enhancement of lipid accumulation in the liver and fat. [BMB Reports 2017; 50(7): 367-372].
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Aciltransferasas/metabolismo , Retículo Endoplásmico/metabolismo , Gotas Lipídicas/metabolismo , Triglicéridos/biosíntesis , Animales , Células COS , Células Cultivadas , Chlorocebus aethiops , Células HEK293 , Humanos , Ratones , N-AcetilglucosaminiltransferasasRESUMEN
Alcohol consumption is one of the major causes of hepatic steatosis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Ethanol metabolism alters the NAD(+)/NADH ratio, thereby suppressing the activity of sirtuin family proteins, which may affect lipid metabolism in liver cells. However, it is not clear how long-term ingestion of ethanol eventually causes lipid accumulation in liver. Here, we demonstrate that chronic ethanol ingestion activates peroxisome proliferator-activated receptor γ (PPARγ) and its target gene, monoacylglycerol O-acyltransferase 1 (MGAT1). During ethanol metabolism, a low NAD(+)/NADH ratio repressed NAD-dependent deacetylase sirtuin 1 (SIRT1) activity, concomitantly resulting in increased acetylated PPARγ with high transcriptional activity. Accordingly, SIRT1 transgenic mice exhibited a low level of acetylated PPARγ and were protected from hepatic steatosis driven by alcohol or PPARγ2 overexpression, suggesting that ethanol metabolism causes lipid accumulation through activation of PPARγ through acetylation. Among the genes induced by PPARγ upon alcohol consumption, MGAT1 has been shown to be involved in triglyceride synthesis. Thus, we tested the effect of MGAT1 knockdown in mice following ethanol consumption, and found a significant reduction in alcohol-induced hepatic lipid accumulation. These results suggest that MGAT1 may afford a promising approach to the treatment of fatty liver disease.
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Aciltransferasas/metabolismo , Hígado Graso Alcohólico/terapia , PPAR gamma/metabolismo , Aciltransferasas/genética , Animales , Etanol/metabolismo , Hígado Graso Alcohólico/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , NAD/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
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.
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Aciltransferasas/metabolismo , Hepatocitos/enzimología , Metabolismo de los Lípidos , PPAR gamma/metabolismo , Secuencia de Bases , Células Cultivadas , Cartilla de ADN , Ensayo de Cambio de Movilidad Electroforética , Hepatocitos/metabolismo , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic ß-cell and the exact mechanisms associated with ethanol-mediated ß-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic ß-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic ß-cell dysfunction and metabolic syndrome.
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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.