Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice

Hsu, Ming Fo; Koike, Shinichiro; Mello, Aline Haas de; Nagy, Laura E.; Haj, Fawaz G.

doi:10.1016/j.redox.2020.101658

Cited by 22 publications

(13 citation statements)

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“…Deficiency of PTP1B is also reported to effectively restore the dampened phosphorylation of AMPK and hyperactivate phosphorylation of mTOR and Raptor in mice fed with HFD ( Kandadi et al, 2015 ; Xu et al, 2019 ). Considering the low expressions of NF-κB and NOX2 and inhibited inflammation in liver-specific PTP1B knockout mice ( Hsu et al, 2020 ), we speculated whether these changes are related to AMPK activation in livers and our hypothesis remains to be identified in the future. In the current study, we found that FA relived hepatic fibrosis by, at least partly, directly binding to and acting as a PTP1B antagonist, which further confirmed our hypothesis that the binding ability between FA and AMPK was weaker than that between FA with PTP1B ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, researches concerning the role of PTP1B in fibrotic liver injury have stepped into a new stage. Specific liver-knockout of PTP1B protected mice from chronic alcohol plus binge-induced oxidative stress, liver fibrosis and inflammation via the inhibition of nuclear factor kappa B (NF-κB) and reduction of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and NOX4 expression ( Hsu et al, 2020 ). Consistent with prior findings, PTP1B overexpression notably hindered the inactivation of HSC-T6 cells, as manifested by restoring the levels of collagen 1 (COL1) and alpha-smooth muscle actin (α-SMA) ( Chen et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

Xue

Fan

et al. 2021

Front. Pharmacol.

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Chronic inflammation in response to persistent exogenous stimuli or damage results in liver fibrosis, which subsequently progresses into malignant liver diseases with high morbidity and mortality. Ferulic acid (FA) is a phenolic acid widely isolated from abundant plants and exhibits multiple biological activities including anti-oxidant, anti-inflammation and enhancement of immune responses. Adenosine monophosphate-activated protein kinase (AMPK) functions as a critical energy sensor and is regulated through the phosphorylation of liver kinases like LKB1 or dephosphorylation by protein tyrosine phosphatases (PTPs). However, the role of FA in carbon tetrachloride (CCl4)-induced chronic inflammation and liver fibrosis and AMPK activation has not been elucidated. Here we reported that FA ameliorated CCl4-induced inflammation and fibrotic liver damage in mice as indicated by reduced levels of serum liver function enzyme activities and decreased expression of genes and proteins associated with fibrogenesis. Additionally, FA inhibited hepatic oxidative stress, macrophage activation and HSC activation via AMPK phosphorylation in different liver cells. Mechanically, without the participation of LKB1, FA-induced anti-inflammatory and anti-fibrotic effects were abrogated by a specific AMPK inhibitor, compound C. Combining with the results of molecular docking, surface plasmon resonance and co-immunoprecipitation assays, we further demonstrated that FA directly bound to and inhibited PTP1B, an enzyme responsible for dephosphorylating key protein kinases, and eventually leading to the phosphorylation of AMPK. In summary, our results indicated that FA alleviated oxidative stress, hepatic inflammation and fibrotic response in livers through PTP1B-AMPK signaling pathways. Taken together, we provide novel insights into the potential of FA as a natural product-derived therapeutic agent for the treatment of fibrotic liver injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

Xue

Fan

et al. 2021

Front. Pharmacol.

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“…Oxidative stress has been identified as a potential mechanism of ALD, which is caused by the imbalance between antioxidant capacity and reactive oxygen species (ROS) (Hsu et al, 2020). The nuclear factor-erythroid 2-related factor (Nrf2) is considered to be a cytoprotective factor, and to a certain extent it exerts antioxidant and anti-inflammatory effects through heme oxygenase-1 (HO-1) and their products (Loboda et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

et al. 2021

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Alcoholic liver disease (ALD) is one of the main causes of death in chronic liver disease. Oxidative stress and pyroptosis are important factors leading to ALD. Bromodomain-containing protein 4 (BRD4) is a factor that we have confirmed to regulate ALD. As a phenolic acid compound, sinapic acid (SA) has significant effects in antioxidant, anti-inflammatory and liver protection. In this study, we explored whether SA regulates oxidative stress and pyroptosis through BRD4 to play a protective effect in ALD. Male C57BL/6 mice and AML-12 cells were used for experiments. We found that SA treatment largely abolished the up-regulation of BRD4 and key proteins of the canonical pyroptosis signalling in the liver of mice fed with alcohol, while conversely enhanced the antioxidant response. Consistantly, both SA pretreatment and BRD4 knockdown inhibited oxidative stress, pyroptosis, and liver cell damage in vitro. More importantly, the expression levels of BRD4 and pyroptosis indicators increased significantly in ALD patients. Molecule docking analysis revealed a potent binding of SA with BRD4. In conclusion, this study demonstrates that SA reduces ALD through BRD4, which is a valuable lead compound that prevents the ALD process.

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“…Mouse hepatocyte isolation and culture were performed as reported 58 with few modifications, as we described. 59 For the measurement of ROS, the primary hepatocytes were incubated with 6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (50 mg/24-well plates; Thermo Scientific) for 30 minutes at 37ºC. Then, the cells were treated with ethanol (100 mmol/L) for an additional 60 minutes at 37ºC.…”

Section: Primary Hepatocyte Isolation and Culturementioning

confidence: 99%

Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease

Mello

Hsu

Koike

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored. METHODS:To decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2 fl/fl ). Alb-Cre; Ephx2 fl/fl and control (Ephx2 fl/fl ) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model. RESULTS:We observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2 fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding.CONCLUSIONS: These findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach.

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Hepatic protein-tyrosine phosphatase 1B disruption and pharmacological inhibition attenuate ethanol-induced oxidative stress and ameliorate alcoholic liver disease in mice

Cited by 22 publications

References 71 publications

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease

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