Characterization of ALDH2-deficient alcohol-associated liver disease (duodenum RNA seq)
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ABSTRACT:
PROVIDER: PRJNA1215761 | ENA |
REPOSITORIES: ENA
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Project description:Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme to detoxify the ethanol first metabolite acetaldehyde. Approximately 8% world population have inactive ALDH2 and have facial flushing due to high levels of acetaldehyde after alcohol consumption. Alcohol-associated liver disease (ALD) and hepatocellular carcinoma (HCC) in those with inactive ALDH2 have not been characterized. ALD pathogeneses in these individuals are likely very different from those with normal ALDH2, different diagnosis criteria and treatment are required for these two populations. Here we studied ALD in inactive Aldh2 knockin (Aldh2KI) mice with chronic ethanol feeding.
2025-07-16 | GSE288043 | GEO
Project description:The tumor suppressor p53 is critical for tumor suppression and other biological events. Yet, the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating the ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for oxidization of alcohol. Through repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl-CoA and histone acetylation, leading to the inhibition of the stearoyl-CoA desaturase-1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer, and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53 deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, hepatic specific knockdown of SCD1 diminishes ethanol-induced fatty liver caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wildtype mice, while has mild effect on p53-/- or ALDH2-/- mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol-induced fatty liver, and uncover pyruvate as a natural regulator of ALDH2.
2023-02-08 | GSE222743 | GEO
Project description:This study investigates the role of Aldehyde Dehydrogenase 2 (ALDH2) in the pathogenesis of liver fibrosis. We performed gene expression profiling of liver tissues from wild-type (WT) and Aldh2 knockout mice subjected to a chronic fibrosis model. This dataset aims to identify molecular mechanisms and transcriptomic alterations associated with ALDH2 deficiency in the context of alcohol- and CCl4-induced liver fibrosis.
2026-07-05 | GSE317551 | GEO
Project description:BACKGROUND: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury, but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. Acetaldehyde dehydrogenase 2 (ALDH2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting around 40% of East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. METHODS: A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending (LAD) coronary artery ligation was conducted on wild-type, ALDH2*2, and mice with cardiomyocyte-specific knockdown of eukaryotic translation initiation factor 3 subunit E (eIF3E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma, mouse serum samples, mouse heart tissues, and primary cardiac myocytes. RESULTS: Human ALDH2*2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in plasma through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as Coenzyme Q10 (CoQ10) and tetrahydrobiopterin (BH4). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart functions and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, while ferroptosis-related markers, including Transferrin receptor (TFRC) and Acyl-CoA synthetase long-chain family member 4 (ACSL4), were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents the eIF3E-eIF4G1-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex through releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (e.g., TFRC, ACSL4, and UAP1) containing the GAGGACR (R: represents A/G) motif to promote ferroptosis. Consistently, cardiomyocyte-specific eIF3E knockdown restored ALDH2*2 cardiac function by attenuating ferroptosis in MI. CONCLUSIONS: ALDH2*2 aggravates acute heart failure post-MI through promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocytes ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers. Key Words: ALDH2, myocardial infarction, eIF3E, ferroptosis, protein translation
2026-03-11 | GSE305516 | GEO
Project description:ALDH2 activator, Alda-1, is able to increase the catalytic activity of ALDH2. ALDH2 expression negatively correlates with obesity in mice while 4-HNE accumulation is positively associated with obesity and is increased in terminal adipocyte differentiation. We compared the difference of transcription profile between ethanol (EtOH)-treated and Alda-1-treated cells in induced adipocyte differentiation of 3T3-L1 pre-adipocytes.
2016-09-07 | E-MTAB-4936 | biostudies-arrayexpress
Project description:Hfe disruption in the mouse leads to experimental hemochromatosis by a mechanism which remains elusive. Evidence for at least five modifier genes has been obtained. These account for the higher iron load of Hfe-deficient D2 mice compared to B6 mice. Gene expression profling was used to clarify the mechanism of Hfe action and to identify potential modifier genes. Experiment Overall Design: Liver and duodenum were obtained from wild-type and Hfe-deficient B6 and D2 mice (three mice per strain/genotype combination).
2008-04-04 | E-GEOD-7357 | biostudies-arrayexpress
Project description:With domain focused CRISPR screen, we revealed Fanconi anemia (FA) proteins UBE2T (an E2) and FANCL (an E3) as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxic effects of endogenous aldehydes. We provide evidence that DNA hypermethylation and transcriptional silencing of ALDH2 occur in a recurrent manner in human AML patient samples, which is sufficient to confer FA pathway dependency in this disease. Taken together, our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.
2021-03-25 | GSE169586 | GEO
Project description:We investigated the ALDH2*2 genetic polymorphism and its underlying mechanisms for the first time in a human model system of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation confers elevated levels of reactive oxygen species (ROS) and toxic aldehydes such as 4HNE, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. ALDH2 exerts control of cell survival decisions via modulation of oxidative stress levels. This regulatory circuitry was found to be dysfunctional in the loss-of-function ALDH2*2 genotype, causing upregulation of apoptosis in cardiomyocytes following ischemic insult. These results reveal a novel function of the metabolic enzyme ALDH2 in modulation of cell survival decisions. Molecular mechanism of increased ischemic damage in cardiomyocytes of ALDH2*2 genotype.
2014-07-07 | E-GEOD-59100 | biostudies-arrayexpress
Project description:We demonstrate that ALDH2 knockdown increased multiple canonical pathways and transcriptions factors We used microarrays to analyze the potential mechanism by which ALDH2 regulates gene expression.
2025-02-19 | GSE253622 | GEO
Project description:Tubular epithelial cells (TECs), viewed as the initiating factor in renal fibrosis, undergo a transition from re-absorptive to pro-fibrotic phenotype during chronic kidney disease (CKD) progression. Serving as a critical energy source, Free fatty acid (FFA) metabolism disruption results in injured TECs. Nevertheless, mechanisms underlying pathological FFA metabolism in injured TECs remain unclear. We observed an inverse correlation between ALDH2 expression in TECs and lipid deposition in the renal tissues from CKD patients. To determine whether ALDH2 protects against fibrosis via regulating FFA metabolism, we generated TEC–specific ALDH2 knockout (Aldh2TEC-KO) mice, and observed exacerbated fibrosis and lipid deposition in the renal tissues of Aldh2TEC-KO mice in two different CKD models. Mechanically, we verified that ALDH2 facilitated the formation of PPARα/RXRα heterodimer via nuclear translocation, while ALDH2 deficiency hindered that process, suppressed PPARα/RXRα complex activation, and disrupted fatty acid oxidation. Notably, Fenofibrate, the PPARα-specific agonist, failed to alleviate fibrosis or lipid deposition in the renal tissues from Aldh2TEC-KO mice, indicating that ALDH2 deficiency attenuated Fenofibrate's efficacy. Furthermore, the ALDH2 E487K mutation similarly impaired FFA metabolism and promoted fibrotic phenotype. Together, this work uncovers ALDH2 as a novel FAO regulator and an influencing factor of Fenofibrate therapeutic efficacy in CKD.
2026-08-05 | GSE306861 | GEO