A Promoter Polymorphism in the ALDH2 Gene Affects Its Basal and Acetaldehyde/Ethanol-Induced Gene Expression in Human Peripheral Blood Leukocytes and HepG2 Cells

Kimura, Yukiko; Nishimura, Fusae; Abe, Shuntaro; Fukunaga, Tetsuo; Tanii, Hideji; Saijoh, Kiyofumi

doi:10.1093/alcalc/agn123

Cited by 16 publications

(16 citation statements)

References 31 publications

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“…Furthermore, ALDH2 protein expression was lower in patients with the G-allele of rs886205, compared to patients without it on day 1 of withdrawal. As known from previous studies, Gallele-directed impairment of basal ALDH2 gene transcription was shown to be tightly linked to the presence of the respective promoter region upstream of the polymorphic site, as promoter constructs lacking G-allele and the upstream region did not cause decreased promoter activity [10] . With the data presented here, we provide novel information concerning a putative molecular mechanism for the modulation of ALDH2 protein expression involving epigenetic mechanisms contributing to reported health risks due to genetic disposition by rs886205 and combined heavy alcohol consumption [8,9] .…”

Section: Discussionsupporting

confidence: 63%

“…Furthermore, the Gallele is known to decrease basal levels of ALDH2 promoter activity and gene transcription both in vitro and in vivo. Interestingly, a specific promoter region upstream the ATG codon of the ALDH2 gene exerts a negative regulatory function on basal ALDH2 promoter activity and mRNA levels in the co-presence of the G-allele of rs886205, while no decrease of basal ALDH2 gene transcription can be assessed in the presence of the A-allele [10] .…”

Section: Introductionmentioning

confidence: 99%

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Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients

Nassab

Rhein²,

Hagemeier³

et al. 2015

Eur Addict Res

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Acetaldehyde, the carcinogenic metabolite of ethanol known to provoke aversive symptoms of alcohol consumption, is predominantly eliminated by aldehyde dehydrogenase 2 (ALDH2). Reduced ALDH2 activity correlates with low alcohol tolerance and low risk for alcohol dependence. The ALDH2 promoter polymorphism rs886205 (A>G) is associated with decreased promoter activity, but a molecular mechanism and allele-dependent ALDH2 protein expression has not been described yet. On the basis of allele-dependent epigenetic effects, we analyzed the rs886205 genotype, methylation rates of cytosine-phosphatidyl-guanine (CpG)-sites within a regulatory promoter region and ALDH2 protein levels in 82 alcohol-dependent patients during a 2-week withdrawal and compared them to 34 matched controls. Patients without the G-allele of rs886205 showed higher methylation of the promoter region than controls and readily adapted epigenetically as well as on protein level during withdrawal, while patients with the G-allele displayed retarded methylation readjustment and no change in ALDH2 protein levels. Our data provide novel insights into an unknown genetic-epigenetic interaction, revealing impaired ALDH2 protein expression in patients with the G-allele of rs886205. Additionally, we checked for an association between rs886205 and protection against alcohol dependence and found a trend association between the G-allele and protection against alcohol dependence that needs replication in a larger Caucasian cohort.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients

Nassab

Rhein²,

Hagemeier³

et al. 2015

Eur Addict Res

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show abstract

“…As a response to enhance ethanol catabolism, the upregulation of ALDH2 expression has often been observed in several cases of ethanol exposure. For instance, ALDH2 mRNA of peripheral blood leukocytes increases following alcohol ingestion (0.4 g/kg body weight) in healthy young subjects (Kimura et al 2009). In postmortem brain of alcohol-related disorders, elevated expression levels of ALDH2 were observed in the prefrontal cortex (Zhang et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

Wang

Song

Zhang

et al. 2017

Cell Stress and Chaperones

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Alcohol abuse is a risk factor for a distinct form of congestive heart failure, known as alcoholic cardiomyopathy (ACM). Here, we investigate how microRNAs may participate in the induction of cardiomyocyte apoptosis associated with ethanol exposure in vitro. Increasing the concentrations of ethanol to primary rat cardiomyocytes resulted in elevated apoptosis assessed by annexin V and propidium iodide staining, and reduced expression of an enzyme for alcohol detoxification aldehyde dehydrogenase 2 (ALDH2). These ethanol effects were accompanied by a substantial elevation of miR378a-5p. Driving miR-378a-5p overexpression in cardiomyocytes decreased ALDH2. The specific interaction of miR-378a-5p with the 3'UTR of ALDH2 was examined by luciferase reporter assays, and we found that miR-378a-5p activity depends on a complementary base pairing at the 3′-UTR region of ALDH2 mRNA. Finally, ethanol-induced apoptosis in cardiomyocytes was attenuated in the presence of anti-miR378a-5p. Collectively, these data implicate a likely involvement of miR-378a-5p in the stimulation of cardiomyocyte apoptosis through ALDH2 gene suppression, which might play a potential role in the pathogenesis of ACM.

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“…In vitro and in vivo studies show that regulation of ALDH2 activity can affect cellular response to oxidative stress [8,9]. ALDH2 activity can be affected by gene regulation [10] or post-translational modifications [11][12][13]. For example, ALDH2 can be directly deacetylated by SIRT3 leading to enzymatic inactivation of ALDH2 [13].…”

Section: Introductionmentioning

confidence: 99%

Acetylation‐dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute ethanol‐induced eNOS activation

Xue

Meng

et al. 2011

FEBS Letters

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Edited by Stuart Ferguson Keywords:Aldehyde dehydrogenase 2 Acetylation Endothelial nitric-oxide synthase Ethanol Reactive oxygen species SIRT3 a b s t r a c tModerate alcohol consumption has beneficial effects on endothelial nitric-oxide synthase (eNOS) activation, which can engender an array of anti-atherogenic actions. Here we show that in human aortic endothelial cells (HAECs), rapid activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) mediates ethanol-induced eNOS activation by preventing reactive oxygen species (ROS) accumulation. Furthermore, activation of ALDH2 by ethanol is due to its hyperacetylation by SIRT3 inactivation. These data suggest that ethanol-induced eNOS activation in HAECs may be dependent on ALDH2 hyperacetylation by SIRT3 inactivation.

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A Promoter Polymorphism in the ALDH2 Gene Affects Its Basal and Acetaldehyde/Ethanol-Induced Gene Expression in Human Peripheral Blood Leukocytes and HepG2 Cells

Cited by 16 publications

References 31 publications

Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients

Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

Acetylation‐dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute ethanol‐induced eNOS activation

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