Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

Krüger, Janine; Wellnhofer, Ernst; Meýborg, Heike; Stawowy, Philipp; Östman, Arne; Kintscher, Ulrich; Kappert, Kai

doi:10.1002/2211-5463.12000

Cited by 14 publications

(11 citation statements)

References 45 publications

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“…Sodium stibogluconate, a specific SHP-1 inhibitor 24 , were administered daily (20 mg/kg/day by intraperitoneal injection) in the CCl 4 model for 2 weeks and in the BDL model for 1 week to investigate the effect of SHP-1 inhibition on fibrogenesis. All experimental animal procedures were in accordance with protocols approved by the Institutional Laboratory Animal Care and Use Committee of National Taiwan University.…”

Section: Methodsmentioning

confidence: 99%

Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis

Shiau²,

Jao

et al. 2017

Sci Rep

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This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)–signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1–STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery.

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Section: Methodsmentioning

confidence: 99%

Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis

Shiau²,

Jao

et al. 2017

Sci Rep

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“…Apart from genetic deletion, the pharmacological inhibition of SHP-1 using sodium stibogluconate, a known inhibitor of SHP-1, was efficient in ameliorating the metabolic phenotype in a mouse model of high-fat-diet (HFD)-induced insulin resistance 12 . Additionally, the anti-hyperglycemic and anti-inflammatory actions of metformin in an obese insulin-resistant mouse model were found to be associated with reduced SHP-1 expression and activity in AT 13 .…”

Section: Introductionmentioning

confidence: 99%

Targeted SHP-1 Silencing Modulates the Macrophage Phenotype, Leading to Metabolic Improvement in Dietary Obese Mice

Sharma

Ahmad

Yavvari

et al. 2019

Molecular Therapy - Nucleic Acids

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Chronic over-nutrition promotes adipocyte hypertrophy that creates inflammatory milieu leading to macrophage infiltration and their phenotypic switching during obesity. The SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) has been identified as an important player in inflammatory diseases involving macrophages. However, the role of SHP-1 in modulating the macrophage phenotype has not been elucidated yet. In the present work, we show that adipose tissue macrophage (ATM)-specific deletion of SHP-1 using glucan particle-loaded siRNA improves the metabolic phenotype in dietary obese insulin-resistant mice. The molecular mechanism involves AT remodeling via reducing crown-like structure formation and balancing the pro-inflammatory (M1) and anti-inflammatory macrophage (M2) population. Therefore, targeting ATM-specific SHP-1 using glucan-particle-loaded SHP-1 antagonists could be of immense therapeutic use for the treatment of obesity-associated insulin resistance.

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“…As expected, HFD time-dependently induced obesity, changes in body composition, and reduced glucose tolerance and insulin sensitivity [38–40]. Clinical observations have shown that diabetics have a higher risk for development and prevalence of PAH [10, 14, 41], with the causal and underlying mechanism yet to be established.…”

Section: Discussionmentioning

confidence: 76%

Pulmonary arterial remodelling by deficiency of peroxisome proliferator-activated receptor-γ in murine vascular smooth muscle cells occurs independently of obesity-related pulmonary hypertension

et al. 2019

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Background Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. Methods Wild-type (WT) and VSMC-specific PPARγ-knockout (Sm Pparγ −/− ) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. Results HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and Sm Pparγ −/− mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and Sm Pparγ −/− mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. Conclusions Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization.

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Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

Cited by 14 publications

References 45 publications

Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis

Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis

Targeted SHP-1 Silencing Modulates the Macrophage Phenotype, Leading to Metabolic Improvement in Dietary Obese Mice

Pulmonary arterial remodelling by deficiency of peroxisome proliferator-activated receptor-γ in murine vascular smooth muscle cells occurs independently of obesity-related pulmonary hypertension

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