PTP1B promotes macrophage activation by regulating the NF-κB pathway in alcoholic liver injury

Yang, Lei; Sun, Ying‐Yin; Liu, Yaru; Yin, Na-Na; Bu, Fang-tian; Hou, Yu; Du, Xiao‐Sa; Li, Jun; Huang, Cheng

doi:10.1016/j.toxlet.2019.11.001

Cited by 35 publications

(19 citation statements)

References 44 publications

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“…2 ). Consistent with this observation, it was recently reported that PTP1B silencing attenuates alcohol and LPS-induced inflammatory response and NF-κB signaling in macrophages, whereas overexpression induces inflammation [ 26 ]. PTP1B is an established modulator of the inflammatory response but is likely to be a tissue- and stimulus-dependent [ 55 ].…”

Section: Discussionsupporting

confidence: 75%

“…Additionally, binge drinking increases hypothalamic PTP1B and induces systemic insulin resistance in rats, which is prevented by the administration of a PTPB inhibitor [ 25 ]. Moreover, PTP1B modulates NF-κB signaling and enhances macrophage activation under the ethanol challenge [ 26 ]. However, knowledge gaps persist, including the role of hepatic PTP1B in ALD, the underlying molecular mechanism, and the suitability of this phosphatase as a therapeutic target for this disease.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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Alcoholic liver disease (ALD) is a major health problem and a significant cause of liver-related death. Currently, the mainstay for ALD therapy is alcohol abstinence highlighting the need to develop pharmacotherapeutic approaches. Protein-tyrosine phosphatase 1B (PTP1B) is an established regulator of hepatic functions, but its role in ALD is mostly unexplored. In this study, we used mice with liver-specific PTP1B disruption as well as pharmacological inhibition to investigate the in vivo function of this phosphatase in ALD. We report upregulation of hepatic PTP1B in the chronic plus binge mouse model and, importantly, in liver biopsies of alcoholic hepatitis patients. Also, mice with hepatic PTP1B disruption attenuated ethanol-induced injury, inflammation, and steatosis compared with ethanol-fed control animals. Moreover, PTP1B deficiency was associated with decreased ethanol-induced oxidative stress in vivo and ex vivo . Further, pharmacological modulation of oxidative balance in hepatocytes identified diminished oxidative stress as a contributor to the salutary effects of PTP1B deficiency. Notably, PTP1B pharmacological inhibition elicited beneficial effects and mitigated hepatic injury, inflammation, and steatosis caused by ethanol feeding. In summary, these findings causally link hepatic PTP1B and ALD and define a potential therapeutic target for the management of this disease.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…When the body's intake of alcohol exceeds the metabolic rate, the excess will accumulate in the blood, leading to changes in normal body functions, and even a binge drinking can cause obvious body damage. Most acute alcoholic liver injury refers to toxic pathological damage to the liver caused by short-term heavy drinking; its incidence and the mortality rate are increasing year by year, and the research has attracted increasing attention (Yang et al 2020). Alcoholic liver disease (ALD) may develop from hepatic steatosis to alcoholic hepatitis without intervention, and eventually lead to liver fibrosis, alcoholic cirrhosis and even liver cancer (Baghy et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Taxifolin, a novel food, attenuates acute alcohol-induced liver injury in mice through regulating the NF-κB-mediated inflammation and PI3K/Akt signalling pathways

Ding

Zhao

Chen

et al. 2021

Pharmaceutical Biology

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Context: Taxifolin (TAX) has effective anti-inflammatory, antioxidant and hepatoprotective activities, but its potential mechanism has not been revealed. Objective: To evaluate the potential protective effect of TAX on acute alcohol-induced liver injury in mice. Materials and methods: Alcoholic liver injury model was established by oral alcohol in mice, and randomly distributed in five groups (n ¼ 10): Normal group (oral saline only); Alcohol group (concentration of fermented alcohol: 56%, 6 mL/kg); TAX groups, mice were orally administered with alcohol, and then TAX with doses of 20, 40, 80 mg/kg, respectively. Oral administration was conducted for 6 weeks. Results: TAX treatment illustrated that the level of alanine aminotransferase (ALT) was reduced to 65.90 ± 2.26 U/L and aspartate aminotransferase (AST) to 33.28 ± 5.62 U/L compared with alcohol group (ALT 124.51 ± 4.40 U/L, AST 61.70 ± 4.09 U/L), while superoxide dismutase (SOD) was increased to 49.81 ± 2.39 U/mg and glutathione (GSH) to 8.16 ± 0.44 lmol/g, but MDA was reversed to 2.53 ± 0.24 nmol/ mg. Histopathological examination showed TAX treatment alleviated alcohol-induced hepatocyte necrosis and inflammatory infiltration. Meanwhile, Western blot and rt-PCR indicated TAX reduced IL-6 to 2.49 ± 0.25 pg/mL and TNF-a to 1.79 ± 0.20 pg/mL, and inhibiting NF-jB activation in liver. Moreover, TAX reversed alcohol-induced apoptosis by regulating the expression of PI3K/Akt and its downstream apoptotic factors. Conclusions:The research provides novel evidence of the hepatoprotective effect of TAX on alcoholinduced liver injury, while also providing the possibility for future treatment of alcoholic liver disease.

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“…Furthermore, IL-1β and IL-6 are involved in inflammatory and heat-generating reactions in liver tissues ( 41 ). It was reported that decreases in TNF-α, IL-1β and IL-6 levels could reduce inflammation, oxidative stress and apoptosis ( 42 , 43 ). Previous studies showed that pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 play a key role in the development and progression of alcoholic hepatitis ( 32 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Milk‑derived hexapeptide PGPIPN prevents and attenuates acute alcoholic liver injury in mice by reducing endoplasmic reticulum stress

Chen

et al. 2020

Int J Mol Med

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Bioactive peptides are an emerging area of biomedical research in the study of numerous human diseases, including acute alcoholic liver injury (AALI). To study the role and mechanism of the milk-derived hexapeptide Pro-Gly-Pro-Ile-Pro-Asn (PGPIPN) in preventing and reducing AALI, the present study established a mouse model of AALI. PGPIPN was used as a therapeutic drug, and glutathione (GSH) was used as a positive control. The body and liver weights of mice were measured, and the liver indexes were calculated to observe mice health. The pathological morphology of liver tissues stained with hematoxylin and eosin were examined to analyze hepatic injury, and hepatocyte apoptosis was measured with a TUNEL assay. The concentrations or activities of alanine aminotransferase (ALT), aspartate aminotransferase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, triglyceride, total cholesterol, malondialdehyde, superoxide dismutase and GSH peroxidase (GSH-PX) were detected in serum and/or liver homogenates. The 78 kDa glucose-regulated protein (GRP78), protein kinase R-like (PKR) endoplasmic reticulum kinase (PERK), phosphorylated (p)-PERK, eukaryotic initiation factor 2α (eIF-2α), p-eIF-2α, inositol-requiring enzyme 1α (IRE-1α), spliced X-box binding protein 1 (XBP-1s), C/EBP homologous protein (CHOP), caspase-3 and cleaved caspase-3 proteins associated with endoplasmic reticulum stress in hepatocytes were assessed by western blotting, and RNA levels of XBP-1s, CHOP and caspase-3 genes were assessed by reverse transcription-quantitative PCR. The results suggested that PGPIPN attenuated alcoholic hepatocyte damage in animal models and reduced hepatocyte oxidative stress in a dose-dependent manner. Moreover, PGPIPN reduced endoplasmic reticulum stress by regulating the expression levels of p-PERK, p-eIF-2α, XBP-1s, CHOP, caspase-3 and cleaved caspase-3. Collectively, the present results indicated that PGPIPN, as a potential therapeutic drug for AALI, exerted a protective effect on the liver and could reduce liver damage.

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PTP1B promotes macrophage activation by regulating the NF-κB pathway in alcoholic liver injury

Cited by 35 publications

References 44 publications

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

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

Taxifolin, a novel food, attenuates acute alcohol-induced liver injury in mice through regulating the NF-κB-mediated inflammation and PI3K/Akt signalling pathways

Milk‑derived hexapeptide PGPIPN prevents and attenuates acute alcoholic liver injury in mice by reducing endoplasmic reticulum stress

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