Chronic Ethanol Consumption Inhibits Glucokinase Transcriptional Activity by Atf3 and Triggers Metabolic Syndrome in Vivo

Kim, Ji Yeon; Hwang, Joo-Yeon; Lee, Dae Yeon; Song, E; Park, Keon Jae; Kim, Gyu Hee; Jeong, Eun Ae; Lee, Yoo Jeong; Go, Min Jin; Kim, Dae‐Jin; Lee, Seong Su; Kim, Bong-Jo; Song, Jihyun; Roh, Gu Seob; Gao, Bin; Kim, Won‐Ho

doi:10.1074/jbc.m114.585653

Cited by 43 publications

(34 citation statements)

References 39 publications

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“…This result resembled those from previous laboratory studies . Although several short‐term RCTs with small sample sizes found that moderate alcohol consumption in females improved insulin sensitivity , more research demonstrated that chronic alcohol intake can lead to whole‐body insulin resistance . In contrast, the effects of alcohol on insulin secretion were inconsistent among previous studies .…”

Section: Discussioncontrasting

confidence: 81%

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

et al. 2018

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Aim To assess the causality between alcohol intake, diabetes risk and related traits. Design Mendelian randomization (MR) study. Subgroup analysis, standard instrumental variable analysis and local average treatment effect (LATE) methods were applied to assess linear and non-linear causality. Setting China. Participants A total of 4536 participants, including 721 diabetes cases. Findings Carriage of an ALDH2 rs671 A allele reduced alcohol consumption by 44.63% [95% confidence interval (CI) = -49.44%, À39.37%]. In males, additional carriage of an A allele was significantly connected to decreased diabetes risk for the overall population [odds ratio (OR) = 0.716, 95% CI = 0.567-0.904, P = 0.005] or moderate drinkers (OR = 0.564, 95% CI = 0.355-0.894, P = 0.015). In instrumental variable (IV) analysis, increasing alcohol consumption by 1.7-fold was associated with an incidence-rate ratio of 1.32 (95% CI = 1.06-1.67, P = 0.014) for diabetes risk, and elevated alcohol intake was causally connected to natural log-transformed fasting, 2-hour post-load plasma glucose (β = 0.036, 95% CI = 0.018-0.054; β = 0.072, 95% CI = 0.035-0.108) and insulin resistance [homeostatic model assessment for IR (HOMA-IR] (β = 0.104, 95% CI = 0.039-0.169), but was not associated with beta-cell function (HOMA-beta). In addition, the LATE method did not identify significant U-shaped causality between alcohol consumption and diabetes-related traits. In females, the effects of alcohol intake on all the outcomes were non-significant.Conclusion Among men in China, higher alcohol intake appears to be causally associated with increased diabetes risk and worsened related traits, even for moderate drinkers. This study found no significant U-shaped causality between alcohol consumption and diabetes-related traits. M.P. and J.Z. contributed equally to this study.

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Section: Discussioncontrasting

confidence: 81%

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

et al. 2018

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“…9F) compared to those in niltubacin-treated BK-SS mice. Although we were limited regarding isolation of various cellular subpopulations from drug-treated lungs, it was likely that decreased ET-1 levels arose predominantly from pulmonary endothelial cells, as previously shown (21). Taken together, these data showed that tubacin, a selective inhibitor of histone deacetylase 6 (HDAC6), attenuated ET-1 and PlGF levels in BK-SS mice by upregulating DNM3os/miR-199a2/miR-214 transcription.…”

Section: Binding Of Atf3 Jdp2 and Hdac6 To The Dnm3os Promoter As Dsupporting

confidence: 58%

“…The ATF3 gene, a stress-inducible gene, has been shown to play important roles in several pathological conditions, including host immunity and cancer (19)(20)(21). To de-at Cincinnati Children's Hospital Medical Center.…”

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confidence: 99%

Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression

Zhou

Loberg

et al. 2016

Molecular and Cellular Biology

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P lacenta growth factor (PlGF), an angiogenic growth factor of the vascular endothelial growth factor (VEGF) family, has pleiotropic and redundant roles in development but features prominently in various pathological conditions such as ischemia, angiogenesis, inflammation, atherosclerosis, preeclampsia, and diabetic wound healing (1-9). PlGF expression is induced by hypoxia, erythropoietin, and iron; PlGF effects are manifested via binding to its sole cognate receptor, VEGF receptor 1 (VEGFR-1) (10-13).Recent studies have shown that plasma levels of PlGF are abnormally high in patients with hemolytic anemias, such as in sickle cell disease (SCD) (12,14). Moreover, high plasma PlGF levels correlate with increased incidence of vaso-occlusive events in SCD subjects (12). Consistent with these findings, plasma levels of plasminogen activator inhibitor 1 (PAI-1) and endothelin-1 (ET-1) are high in a mouse model of sickle cell disease, namely, Berkeley sickle (BK-SS) mice, which also show high plasma PlGF levels (15, 16). Conversely, PlGF knockout mice exhibit low plasma PlGF levels and low plasma levels of PAI-1 and ET-1 (15, 16). Furthermore, augmentation of erythroid PlGF expression in normal mice to the levels seen in sickle mice results in increased production of endothelin-1 with associated pulmonary changes, as seen in pulmonary hypertension (PH) in SCD (16); these results were corroborated in a study of 123 patients with SCD (16). Thus, studies in vitro and in vivo support the crucial role of PlGF in upregulating the expression of ET-1 in endothelial cells and associated pulmonary changes characteristic of pulmonary hypertension in SCD.We show that PlGF activates endothelial cells to upregulate the expression of genes such as the ET-1 and PAI-1 genes via activation of hypoxia-inducible factor 1 (HIF-1␣), independently of hypoxia (15,17). Moreover, we have shown that posttranscriptional regulation of ET-1 and PAI-1 is achieved by microRNA 199a2 (miR-199a2), which targets the 3= untranslated region (UTR) of HIF-1␣ mRNA (18).The DNM3 opposite strand (DNM3os) gene produces a noncoding RNA (ncRNA) that serves as the precursor of miR-199a2 and miR-214 (18). This locus is located within an intron of DNM3 and is transcribed from the opposite strand, hence, its designation. Transcription of DNM3os and of cotranscribed miR-199a2/miR-214 is greatly attenuated by PlGF, thus allowing unhindered expansion of HIF-1␣ activity and expression of genes, i.e., the ET-1 and PAI-1 genes, requiring this transcription factor, (18). However, the molecular mechanism of PlGF-mediated downregulation of miR-199a2/miR-214 and DNM3os ncRNA is not fully understood.In the present study, we show that repression of DNM3os in response to PlGF required the participation of activated transcription factor 3 (ATF3), which binds to ATF3 response elements in the DNM3os promoter. The ATF3 gene, a stress-inducible gene, has been shown to play important roles in several pathological conditions, including host immunity and cancer (19-21). To de- Citation...

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“…C). Among them, four considerations prompted us to target ATF3 as the downstream candidate of IRF2BP2: (1) The binding of IRF2BP2 on the ATF3 gene has the highest binding peak score and is in close proximity to the transcription start site (−140 bp); (2) multiple lines of evidences have suggested a pathogenic role of ATF3 in NAFLD and insulin resistance; (3) current understanding indicates a strong preference for IRF2BP2 as a transcription repressor; and (4) ATF3 expression was increased in IRF2BP2 ‐KO cells. Indeed, the up‐regulation of ATF3 mRNA levels in hepatosteatosis models, both in vitro and in vivo , were profoundly reinforced by Irf2bp2 depletion but were conversely suppressed by Irf2bp2 overexpression, as verified by real‐time PCR examinations (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Fang

Zhang

et al. 2020

Hepatology

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Background and Aims Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down‐regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Approach and Results Herein, using gain‐of‐function and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet–induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro. Conclusion IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.

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Chronic Ethanol Consumption Inhibits Glucokinase Transcriptional Activity by Atf3 and Triggers Metabolic Syndrome in Vivo

Cited by 43 publications

References 39 publications

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis

Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

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