Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice

Wang, Han; Zhou, Hao; Zhang, Quanri; Poulsen, Kyle L.; Taylor, Vanessa; McMullen, Megan R.; Czarnecki, Doug; Dasarathy, Dhweeja; Yu, Michael C.; Liao, Yun; Allende, Daniela S.; Chen, Xing; Hong, Lingzi; Zhao, Junjie; Yang, Jinbo; Nagy, Laura E.; Li, Xiaoxia

doi:10.1016/j.jhep.2020.07.016

Cited by 21 publications

(23 citation statements)

References 44 publications

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“…To examine liver inflammation, one of the main characters of ALD, we first used F4/80 immunohistochemistry staining to identify Kupffer cells, the liver resident macrophages that play important role in liver inflammatory responses. Consistent with previous study(Wang et al, 2020), the Kupffer cells were increased in EtOH-fed mice (Figure 3A, B). Moreover, the downward SMF significantly reduced the Kupffer cell numbers in EtOH-fed mice (Figure 3A, B).…”

Section: Resultssupporting

confidence: 93%

“…Our experiments above clearly show that moderate SMFs, especially the downward SMF, can reduce the oxidative stress and have obvious beneficial effects on alcohol-induced mice liver lipid accumulation and toxicity. Here, we wanted to address whether SMFs can reduce the mortality of heavy drinking mice by using an acute EtOH mice model (Wang et al, 2020) (Figure 7A). Thirty-six mice were randomly divided into six groups with either EtOH-fed or pair-fed free access Lieber DeCarli diet, with sham, upward or downward SMF treatment.…”

Section: Resultsmentioning

confidence: 99%

“…All mice were randomly divided into EtOH-fed groups (sham, upward and downward SMF; ethanol diet) and pair-fed groups (sham, upward and downward SMFs; maltodextrin diet). Lieber-DeCarli diets (product L10015 and product L10016) were prepared fresh daily and fed ad libitum to mice using a short-term (chronic EtOH-fed mice model with light drinking) and long-term (acute EtOH-fed mice model with heavy drinking) ethanol feeding protocol of ALD according to the previous report (Wang et al, 2020). The formulas of diets were formulated by Research Diets.…”

Section: Methodsmentioning

confidence: 99%

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A Magnetic Field Prevents Alcoholic Liver Disease by Reducing Oxidative Stress

Chen

et al. 2021

Preprint

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The radical-pair recombination change will affect the generation of free radicals, which can be regulated by static magnetic fields (SMFs) in a SMF setting dependent way. It is well known that alcohol consumption leads to significantly increased free radical levels and health risks, which lacks effective treatment method besides alcohol abstinence. Here we compared different SMF settings and found that a downward SMF of ∼0.1 T with magnetic flux of ∼4.5×10−3 Wb could effectively alleviate alcohol-induced liver damage and lipid accumulation, and improve liver function. The inflammation, reactive oxygen species (ROS) level and oxidative stress were significantly reduced. EPR (electron paramagnetic resonance) experiments also confirmed the reduced amount of free radical by SMF treatment. Moreover, the lifespan of heavy alcohol drinking mice was also significantly changed due to the SMF effects on liver cell ROS level, DNA synthesis and liver cell regeneration. Our study shows that moderate SMFs with specific parameters have great promises to be developed into a physical method to reduce alcohol-induced liver damage in the future.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Magnetic Field Prevents Alcoholic Liver Disease by Reducing Oxidative Stress

Chen

et al. 2021

Preprint

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“…The IRAK1 protein is expressed in the liver (Wang et al 2020). Our data demonstrated that IRAK1 peaked in the maternal liver on DP16 and then declined on DP25 compared to DP16.…”

Section: Discussionmentioning

confidence: 55%

The early stage of pregnancy modulates toll-like receptor signaling in the ovine liver

Gao

Cai

Han

et al. 2021

Journal of Applied Animal Research

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Toll-like receptors (TLRs) participate in maternal immune regulation at multiple maternal-fetal interfaces. The liver is crucial for innate and adaptive immunity during pregnancy. The objective of this study was to measure the expression of genes and proteins related to TLR signaling. In this study, livers were obtained from ewes on day 16 of the estrous cycle, and on days 13, 16 and 25 of gestation, and RT-qPCR, western blot and immunohistochemistry were employed to measure the expression of genes and proteins related to TLR signaling, including TLR2, TLR3, TLR4, TLR5, TLR7, TLR9, myeloid differentiation primary-response protein 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6) and interleukin-1receptor-associated kinase 1 (IRAK1). Our data showed that the expression levels of TLR2, TLR3, TLR5, TLR9 and TRAF6 were increased, but those of TLR4 and TLR7 were decreased in the liver during early pregnancy. In addition, the expression levels of MyD88 and IRAK1 were the highest on days 13 and 16 of pregnancy, respectively, and the MyD88 protein was located in endothelial cells of proper hepatic arteries and portal veins and in hepatocytes. In conclusion, early pregnancy modulates TLR signaling in the maternal liver in sheep, which may participate in maternal immune regulation.

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“…As a result, pathogen‐associated and damage‐associated molecular patterns translocate from the gut lumen to the portal circulation and target the liver. ( 23 ) Therefore, we measured gut permeability in our model. In both genders, ethanol increased portal serum FITC‐dextran but it returned to baseline during resolution from ALD (Supporting Fig.…”

Section: Resultsmentioning

confidence: 99%

The Integrated “Multiomics” Landscape at Peak Injury and Resolution From Alcohol‐Associated Liver Disease

Das

Han

et al. 2021

Hepatol Commun

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Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wildtype mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD. (Hepatology Communications 2021;0:1-28).A ccording to the National Institutes on Alcohol Abuse and Alcoholism, about 88,000 people (62,000 men and 26,000 women) die from alcohol use disorders annually, making alcohol the third leading preventable cause of death in the United States. Overall, alcohol causes more than 5% of the global disease burden worldwide.

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Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice

Cited by 21 publications

References 44 publications

A Magnetic Field Prevents Alcoholic Liver Disease by Reducing Oxidative Stress

A Magnetic Field Prevents Alcoholic Liver Disease by Reducing Oxidative Stress

The early stage of pregnancy modulates toll-like receptor signaling in the ovine liver

The Integrated “Multiomics” Landscape at Peak Injury and Resolution From Alcohol‐Associated Liver Disease

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