Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids

Gao, Yanhang; Zhou, Zhou; Ren, Tianyi; Kim, Seung-Jin; He, Yong; Seo, Wonhyo; Guillot, Adrien; Ding, Yanhua; Wu, Ruihong; Shao, Shuang; Wang, Xiaomei; Zhang, Hong; Wang, Wei; Feng, Dechun; Xu, Mingjiang; Han, Elaine; Zhong, Wei; Zhou, Zhanxiang; Pacher, Pál; Niu, Junqi; Gao, Bin

doi:10.1136/gutjnl-2018-316221

Cited by 50 publications

(62 citation statements)

References 53 publications

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“…Acetaldehyde, which is a major by-product of ethanol, is one of the predominant compounds that are highly toxic to hepatocytes. ALDH2 is a key enzyme for acetaldehyde detoxification in the liver [45]. Moreover, ALDH2 deficiency is associated with increased acetaldehyde and glucocorticoids after alcohol consumption [45].…”

Section: Discussionmentioning

confidence: 99%

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Cryptotanshinone from the Salvia miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways

Nagappan

Kim

Jung

et al. 2019

IJMS

103

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Cryptotanshinone (CT), a diterpene that is isolated from Salvia miltiorrhiza Bunge, exhibits anti-cancer, anti-oxidative, anti-fibrosis, and anti-inflammatory properties. Here, we examined whether CT administration possess a hepatoprotective effect on chronic ethanol-induced liver injury. We established a chronic alcohol feeding mouse model while using C57BL/6 mice, and examined the liver sections with hematoxylin-eosin (H&E) and Oil Red O (ORO) staining. Further, we analyzed the lipogenesis, fatty acid oxidation, oxidative stress, and inflammation genes by using quantitative polymerase chain reaction (qPCR) and immunoblotting in in vivo, and in vitro while using HepG2 and AML-12 cells. CT treatment significantly ameliorated ethanol-promoted hepatic steatosis, which was consistent with the decreased hepatic triglyceride levels. Interestingly, CT activated the phosphorylation of AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and nuclear factor E2-related factor 2 (Nrf2) proteins. Importantly, compound C (AMPK inhibitor) significantly blocked the CT-mediated reduction in TG accumulation, but not Ex52735 (SIRT1 inhibitor), which suggested that CT countering ethanol-promoted hepatic steatosis is mediated by AMPK activation. Furthermore, CT significantly inhibited cytochrome P450 2E1 (CYP2E1) and enhanced both the expression of antioxidant genes and hepatic glutathione levels. Finally, CT inhibited the ethanol-induced inflammation in ethanol-fed mice and HepG2 cells. Overall, CT exhibits a hepatoprotective effect against ethanol-induced liver injury by the inhibition of lipogenesis, oxidative stress, and inflammation through the activation of AMPK/SIRT1 and Nrf2 and the inhibition of CYP2E1. Therefore, CT could be an effective therapeutic agent for treating ethanol-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

“…ALDH2 is a key enzyme for acetaldehyde detoxification in the liver [45]. Moreover, ALDH2 deficiency is associated with increased acetaldehyde and glucocorticoids after alcohol consumption [45]. We measured ADH1 and ALDH2 expression in mouse livers while using qPCR.…”

Section: Discussionmentioning

confidence: 99%

Cryptotanshinone from the Salvia miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways

Nagappan

Kim

Jung

et al. 2019

IJMS

103

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“…21 Th17 cells not only promote liver inflammation and fibrosis in ALD by producing IL-17, 22 but may also help in liver repair by stimulating IL-22 production. 23 Although activated T cells are often detected in ALD and may contribute to disease pathogenesis, excessive alcohol drinking also caused broad immunosuppression 24 including inhibition of T cells via acetaldehyde and glucocorticoids, 25 thereby resulting in an increased risk of bacterial infection in patients with ALD.…”

Section: Key Pointsmentioning

confidence: 99%

Inflammatory pathways in alcoholic steatohepatitis

Gao

Ahmad

Nagy

et al. 2019

Journal of Hepatology

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277

284

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Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro-and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.

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“…The major difficulty is a lack of valid models in which a liver can support viral infection and alcohol metabolism that resembles liver injury caused by alcohol consumption and viral infection in alcoholic patients with chronic hepatitis C [41]. Our previous work demonstrated that alcohol-fed Aldh2 -/mice were less sensitive to concanavalin A-induced T-cell hepatitis than wild-type mice [42]. Further studies suggest that acetaldehyde directly suppresses cytokine production in T cells through the inhibition of aerobic glycolysis or stimulation of corticosterone release, which contributes to the occurrence of suppressed T-cell hepatitis in ethanol-fed Aldh2 -/mice [42].…”

Section: Aldh and Viral Liver Diseasesmentioning

confidence: 99%

“…Our previous work demonstrated that alcohol-fed Aldh2 -/mice were less sensitive to concanavalin A-induced T-cell hepatitis than wild-type mice [42]. Further studies suggest that acetaldehyde directly suppresses cytokine production in T cells through the inhibition of aerobic glycolysis or stimulation of corticosterone release, which contributes to the occurrence of suppressed T-cell hepatitis in ethanol-fed Aldh2 -/mice [42]. Cho et al suggested that the ADH/ALDH pathway also exerts a potent antiviral activity, likely mediated through the catalysis of retinol (ROL) and RA biogenesis, leading to the expression of interferon-stimulated genes (ISGs) [38].…”

Section: Aldh and Viral Liver Diseasesmentioning

confidence: 99%

Aldehyde Dehydrogenase, Liver Disease and Cancer

Wang

et al. 2020

Int. J. Biol. Sci.

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Acetaldehyde dehydrogenase 2 (ALDH2) is the key enzyme responsible for metabolism of the alcohol metabolite acetaldehyde in the liver. In addition to conversion of the acetaldehyde molecule, ALDH is also involved in other cellular functions. Recently, many studies have investigated the involvement of ALDH expression in viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and liver cancer. Notably, ALDH2 expression has been linked with liver cancer risk, as well as pathogenesis and prognosis, and has emerged as a promising therapeutic target. Of note, approximately 8% of the world's population, and approximately 30-40% of the population in East Asia carry an inactive ALDH2 gene. This review summarizes new progress in understanding tissue-specific acetaldehyde metabolism by ALDH2 as well as the association of ALDH2 gene polymorphisms with liver disease and cancer. New research directions emerging in the field are also briefly discussed.

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Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids

Abstract: ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.

Cited by 50 publications

References 53 publications

Cryptotanshinone from the Salvia miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways

Cryptotanshinone from the Salvia miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways

Inflammatory pathways in alcoholic steatohepatitis

Aldehyde Dehydrogenase, Liver Disease and Cancer

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