P53 regulates ethanol metabolism via ALDH2 modulating the development of alcoholic fatty liver disease
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ABSTRACT:
PROVIDER: PRJNA923299 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23063363_1.fastq.gz | Fastqsanger.gz | |||
| SRR23063363_2.fastq.gz | Fastqsanger.gz | |||
| SRR23063364_1.fastq.gz | Fastqsanger.gz | |||
| SRR23063364_2.fastq.gz | Fastqsanger.gz | |||
| SRR23063365_1.fastq.gz | Fastqsanger.gz |
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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: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.
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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.
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Project description:To elucidate the effect of the polyphenols contained in alcoholic beverages on the metabolic stress induced by ethanol consumption, four groups of mice were fed for five weeks on Lieber's diet with or without ethanol, with ethanol plus ellagic acid, and with ethanol plus trans-resveratrol. Alcoholic fatty liver was observed in the group fed the ethanol diet but not in those fed the ethanol plus polyphenol diets. Liver transcriptome analysis revealed that the addition of the polyphenols suppressed the expression of the genes related to cell stress that were up-regulated by ethanol alone. Conversely, the polyphenols up-regulated the genes involved in bile acid synthesis, unsaturated fatty acid elongation, and tetrahydrofolate synthesis that were down-regulated by ethanol alone. Because parts of these genes were known to be regulated by the constitutive androstane receptor (CAR), we performed the same experiment in the CAR-deficient mice. As a result, fatty liver was observed not only in the ethanol group but also with the ethanol plus polyphenol groups. In addition, there was no segregation of the gene expression profiles among these groups. These results provide a molecular basis for the prevention of alcohol-induced stress by the polyphenols in alcoholic beverages.
2014-02-01 | GSE52644 | GEO
Project description:To elucidate the effect of the polyphenols contained in alcoholic beverages on the metabolic stress induced by ethanol consumption, four groups of mice were fed for five weeks on Lieber's diet with or without ethanol, with ethanol plus ellagic acid, and with ethanol plus trans-resveratrol. Alcoholic fatty liver was observed in the group fed the ethanol diet but not in those fed the ethanol plus polyphenol diets. Liver transcriptome analysis revealed that the addition of the polyphenols suppressed the expression of the genes related to cell stress that were up-regulated by ethanol alone. Conversely, the polyphenols up-regulated the genes involved in bile acid synthesis, unsaturated fatty acid elongation, and tetrahydrofolate synthesis that were down-regulated by ethanol alone. Because parts of these genes were known to be regulated by the constitutive androstane receptor (CAR), we performed the same experiment in the CAR-deficient mice. As a result, fatty liver was observed not only in the ethanol group but also with the ethanol plus polyphenol groups. In addition, there was no segregation of the gene expression profiles among these groups. These results provide a molecular basis for the prevention of alcohol-induced stress by the polyphenols in alcoholic beverages. Five-week-old C3H/HeN female mice (CLEA, Japan) were acclimated to the maintenance condition (25°C, 8:00-20:00 day / 20:00-8:00 night cycle and 35~40 % humidity), fed a CE-2 diet (CLEA, Japan), and given water ad libitum for one week. Each group of mice (n=4 for wild type mice analysis and n=3 for CAR decficient mice analysis) was fed Lieber's isocaloric diet (Oriental yeast, Japan) containing water, containing ethanol, containing ethanol and ellagic acid (Fluka Biochemika, Switzerland), or containing ethanol and trans-resveratrol (Sigma, USA) (Supplementary Table 1) for one week at 10:00 ad libitum. Then, the mice were fed each diet at 12 g / day for four weeks (Supplementary Fig. 1A). The approximate intake of each polyphenol was 50 mg / kg body weight / day. At 10:00 of the final day of the experimental period, the animals were anesthetized by diethyl ether, sacrificed by cervial fracture, and the heart blood, and the liver were collected.
2014-02-01 | E-GEOD-52644 | biostudies-arrayexpress
Project description:The tumor suppressor p53 is critical for tumor suppression, but 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. By 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, liver-specific knockdown of SCD1 alleviates ethanol-induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wildtype mice, while it has a 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.
| S-SCDT-10_15252-EMBJ_2022112304 | biostudies-other
Project description:The tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for the oxidization of alcohol. By 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, liver-specific knockdown of SCD1 alleviates ethanol-induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wild-type mice, while it has a 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.
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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.
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2014-11-07 | E-GEOD-63067 | biostudies-arrayexpress
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.
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