Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice

Rubio, Carmen; Puerto, Marta; García-Rodríquez, Juan J.; Lu, Van B.; García-Martínez, Irma; Alén, Rosa; Sanmartín-Salinas, Patricia; Toledo-Lobo, M Val; Sáiz, Jorge; Rupérez, Javier; Barbas, Coral; Menchén, Luís; Gribble, Fiona M.; Reimann, Frank; Guijarro, Luis G.; Carrascosa, J.M.; Valverde, Ángela M.

doi:10.1016/j.molmet.2020.01.018

Cited by 13 publications

(14 citation statements)

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“…Ptpn1 is involved in inflammation by reprogramming macrophage polarization [ 14 , 16 , 33 ]. Mice that are globally deficient for Ptpn1 show enhanced barrier integrity in non-alcoholic steatohepatitis (NASH) [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Tyrosine-protein phosphatase non-receptor type 1 (Ptpn1), also known as protein tyrosine phosphatase 1B (Ptp1b), is a negative regulator of the insulin signalling pathway and has been proposed as a promising drug target to treat over-nutrition and obesity-induced insulin resistance [ 12 , 13 ]. More recently, the role of Ptpn1 in developing chronic inflammatory disorders has been studied [ 14 ]. However, the results are paradoxical.…”

Section: Introductionmentioning

confidence: 99%

“…However, the results are paradoxical. Ptpn1 deficiency were reported to result in enhanced M1 macrophage polarization, exacerbated mucosal inflammation, and impaired intestinal barrier integrity [ [14] , [15] , [16] ]. However, inhibition of Ptpn1 was also known to promote M2 macrophage polarization and prevent excessive inflammation [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Small extracellular vesicles from Ptpn1-deficient macrophages alleviate intestinal inflammation by reprogramming macrophage polarization via lactadherin enrichment

Han¹,

Lu²,

Huang³

et al. 2022

Redox Biology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Small extracellular vesicles from Ptpn1-deficient macrophages alleviate intestinal inflammation by reprogramming macrophage polarization via lactadherin enrichment

Han¹,

Lu²,

Huang³

et al. 2022

Redox Biology

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“…Seeking a causative factor for the onset of inflammation-mediated insulin resistance in BAT, we explored whether endotoxemia was sufficient to trigger pro-inflammatory signaling cascades in this tissue. Based on previous studies [ 63 , 64 ], we injected a non-septic dose of LPS into the WT mice and found a pro-inflammatory signaling signature in BAT similar to that of the db/db mice. Of note, these pathways negatively impact insulin signaling at different levels [ [65] , [66] , [67] ] and are likely responsible for the impairment of IR and AKT phosphorylation in BAT from the LPS-injected or db/db mice.…”

Section: Discussionmentioning

confidence: 99%

Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Escalona-Garrido

Vázquez

Mera³

et al. 2020

Molecular Metabolism

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Objective Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1 Tg+ ) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1 Tg+ ) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1 Tg+ ) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T 3 ) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1 Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T 3 -enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1 Tg+ fully recovered insulin and noradrenergic responses. Conclusions This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.

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“…Mechanisms involved in AMPK activation include activating upstream kinases of AMPK or inactivating dephosphorylated kinases that control the activation of AMPK. The aberrant interplay between protein-tyrosine phosphatases (PTPs), responsible for protein dephosphorylation, and tyrosine kinases affects the function of multiple proteins, disrupts the normal liver function and impacts the progression of chronic liver diseases ( Rubio et al, 2020 ). PTP1B is one of the most critical members of PTPs family and expresses in multiple hepatic cells.…”

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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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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Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice

Cited by 13 publications

References 84 publications

Small extracellular vesicles from Ptpn1-deficient macrophages alleviate intestinal inflammation by reprogramming macrophage polarization via lactadherin enrichment

Small extracellular vesicles from Ptpn1-deficient macrophages alleviate intestinal inflammation by reprogramming macrophage polarization via lactadherin enrichment

Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

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

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