Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance

Toonen, Erik J. M.; Mirea, Andreea-Manuela; Tack, Cees J.; Stienstra, Rinke; Ballak, Dov B.; Diepen, Janna A. van; Hijmans, Anneke; Chavakis, Triantafyllos; Dokter, Wim H.A.; Pham, Christine; Netea, Mihai G.; Dinarello, Charles A.; Joosten, Leo A. B.

doi:10.2119/molmed.2016.00033

Cited by 31 publications

(32 citation statements)

References 21 publications

(25 reference statements)

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“…Disorder of lipid metabolism is a fundamentally pathological conditions in the development of insulin resistance and type 2 diabetes [7]. For instance, lipid accumulation in insulin-target tissues such as liver and muscle contributes to reduction of insulin signaling [42,43]. Previous studies have shown that Lycopene inhibited the pathogenesis of hepatic steatosis [16,31].…”

Section: Discussionmentioning

confidence: 99%

Lycopene Improves Insulin Sensitivity through Inhibition of STAT3/Srebp-1c-Mediated Lipid Accumulation and Inflammation in Mice fed a High-Fat Diet

Zhao-hui

Jia

et al. 2017

Exp Clin Endocrinol Diabetes

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In the past few years, metabolic disorders, such as type 2 diabetes and metabolic syndrome, have reached global prevalence. Lycopene is one of the major carotenoids in tomatoes, watermelons, red grapefruits, and guava. In the current study, using high fat diet (HFD)-fed mice, we investigated the effect of Lycopene on insulin resistance. We showed that diet containing Lycopene significantly prevented HFD-induced increase of fasting blood glucose and insulin level, glucose and insulin intolerance, and decrease of hepatic glycogen content. We found that Lycopene notably prevented the increase of IL-1β, TNFα and CRP levels in mice fed HFD. We showed that Lycopene improved the lipid profiles in HFD-fed mice, as evidenced by decrease of systemic and hepatic TC, TG and LDL, and increase of HDL. Lycopene suppressed the increase of the expression of Srebp-1c, FAS and ACC-1 in mice fed HFD. The administration of Lycopene notably prevented the expression and phosphorylation of STAT3 in livers of mice induced by HFD. The treatment of adenovirus carrying STAT3 significantly suppressed the decrease of Srebp-1c expression induced by Lycopene. Furthermore, enhancement of STAT3 signaling by adenovirus markedly blocked the reduction of fasting blood glucose and insulin level. In conclusion, in the current study, we found that Lycopene prevented STAT3 signaling and inhibited Srebp-1c and downstream gene expression, resulting in inhibition of lipid accumulation, inflammation, insulin resistance and metabolic dysfunction. Overall, the data in the study provide better understanding of the beneficial effects of Lycopene against insulin resistance and metabolic disorder.

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Section: Discussionmentioning

confidence: 99%

Lycopene Improves Insulin Sensitivity through Inhibition of STAT3/Srebp-1c-Mediated Lipid Accumulation and Inflammation in Mice fed a High-Fat Diet

Zhao-hui

Jia

et al. 2017

Exp Clin Endocrinol Diabetes

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“…Also, NE knockout mice have been described to have higher energy expenditure rates, increased body temperature, and increased fatty acid oxidation [16]. In line with these results, PR3/NE knockout mice gained less weight, accumulated less triglycerides in the liver than WT mice fed a HFD, and have decreased mRNA expression of gene-encoding proteins involved in lipogenesis and fatty acid uptake, suggesting a better metabolic profile than WT mice [18]. Since our mouse model is lacking all the genes mentioned above, it is likely that these mice have also a more active basal metabolism and have an improved control of lipid metabolism than WT mice.…”

Section: Discussionmentioning

confidence: 60%

“…Our group has previously shown that double knockout mice deficient in NE/PR3 do gain weight after HFD intervention and showed a certain degree of liver steatosis but significantly less than WT controls fed the same diet. In addition, these mice were protected against the development of adipose tissue inflammation [18]. In contrast, Dixon et al showed that Caspase-1/11 double knockout mice developed HFD- Fig.…”

Section: Discussionmentioning

confidence: 94%

“…They calculated rather good sensitivity and specificity scores for the NE/AAT ratio in order to predict the advanced stages of the disease [17]. Our group has recently shown that, additionally to NE, also PR3 plays an important role in the development of obesity-induced NAFLD and insulin resistance in a mouse model for obesity-induced NAFLD [18]. Furthermore, we have shown that administering human AAT protects against disease development in a mouse model of obesity-induced NAFLD [18].…”

Section: Introductionmentioning

confidence: 99%

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Mice Deficient in the IL-1β Activation Genes Prtn3, Elane, and Casp1 Are Protected Against the Development of Obesity-Induced NAFLD

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Inflammatory pathways contribute to disease pathogenesis; however, regulation of the underlying mechanism is not completely understood. IL-1β, a proinflammatory cytokine, participates in the development and progression of NAFLD. To become bioactive, IL-1β requires enzymatic processing. Mechanisms that activate IL-1β include the classical NLRP3 inflammasome-caspase-1 and the neutrophil serine proteases, neutrophil elastase, and proteinase-3. Several studies have shown that both caspase-1 and the neutrophil serine proteases are important for NAFLD development. However, it is unknown whether these pathways interact and if they have a synergistic effect in promoting NAFLD. In the present study, we developed a novel and unique mouse model by intercrossing caspase-1/ 11 knockout mice with neutrophil elastase/proteinase-3 double knockout mice. Subsequently, these mice were examined regarding the development of high-fat diet-induced NAFLD. Our results show that mice deficient in caspase-1, neutrophil elastase, and proteinase-3 were protected from developing diet-induced weigh gain, liver steatosis, and adipose tissue inflammation when compared with controls. We conclude that pathways that process pro-IL-1β to bioactive IL-1β play an important role in promoting the development of NAFLD and obesity-induced inflammation. Targeting these pathways could have a therapeutic potential in patients with NAFLD.

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“…Their main metabolic functions included lipid and glucose metabolism, transport/metabolism of vitamins and minerals, immune system function, blood clotting, and acute phase reactions (Bisoendial et al, 2015;Calder et al, 2013;Campenhout, Campenhout, & Lagrou, 2003;Carter & Worwood, 2007;Clerc et al, 2016;Dabrowska, Tarach Toonen et al, 2016;UniProt, 2016UniProt, , 2017aUniProt, , 2017bWalldius & Jungner, 2004;Wang et al, 2015;Wu & Lyons, 2011). Their main metabolic functions included lipid and glucose metabolism, transport/metabolism of vitamins and minerals, immune system function, blood clotting, and acute phase reactions (Bisoendial et al, 2015;Calder et al, 2013;Campenhout, Campenhout, & Lagrou, 2003;Carter & Worwood, 2007;Clerc et al, 2016;Dabrowska, Tarach Toonen et al, 2016;UniProt, 2016UniProt, , 2017aUniProt, , 2017bWalldius & Jungner, 2004;Wang et al, 2015;Wu & Lyons, 2011).…”

Section: Discussionmentioning

confidence: 99%

Metabo groups in response to micronutrient intervention: Pilot study

Coelho-Landell

Salomão

Almada

et al. 2019

Food Science & Nutrition

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Micronutrients and their metabolites are cofactors in proteins involved in lipid metabolism. The present study was a subproject of the Harmonized Micronutrient Project (ClinTrials.gov # NCT01823744). Twenty participants were randomly selected from 136 children and adolescents that consumed a daily dose of 12 vitamins and 5 minerals supplementation for 6 weeks. The 20 individuals were divided into two pools of 10 individuals, according to their lipid profile at baseline (Pool 1 with lower triglycerides, LDL, and VLDL). The individuals were analyzed at baseline, after 6 weeks of daily supplementation, and after 6 weeks of a washout period in relation to anthropometric, body composition, food intake, lipid profile, micronutrient levels, and iTRAQ proteomic data. Genetic ancestry and its association with vitamin serum levels were also determined. After supplementation, LDL levels decreased while alpha-tocopherol and pantothenic acid levels increased in pool 2; lipid profiles in pool 1 did not change but had higher plasma levels of pantothenic acid, pyridoxal, and pyridoxic acid. In pool 2, expression of some proteins increased, and expression of other ones decreased after intervention, while in pool 1, the same proteins responded inversely or did not change their levels. Plasma alpha-tocopherol and Native American genetic ancestry explained a significant fraction of LDL plasma levels at baseline and in response to the intervention. After intervention, changes in expression of alpha-1 antitrypsin, haptoglobin, Ig alpha-1 chain C region, plasma protease C1 inhibitor, alpha-1-acid glycoprotein 1, fibrinogen alpha, beta, and gamma-chain in individuals in pool 2 may be associated with levels of LDL and vitamin E. Vitamin E and Native American genetic ancestry may also be implicated in changes of vitamin E and LDL levels. The results of this pilot study must be validated in future studies with larger sample size or in in vitro studies. 20 participants were divided into two metabolic groups according only to their lipid profiles: individuals in pool 1 (n = 10) had lower triglycerides, LDL, and VLDL levels, and individuals in pool 2 K E Y W O R D S genetic ancestry, intervention study, lipid profile, metabolomics, proteomics, Vitamin plasma levels

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Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance

Cited by 31 publications

References 21 publications

Lycopene Improves Insulin Sensitivity through Inhibition of STAT3/Srebp-1c-Mediated Lipid Accumulation and Inflammation in Mice fed a High-Fat Diet

Lycopene Improves Insulin Sensitivity through Inhibition of STAT3/Srebp-1c-Mediated Lipid Accumulation and Inflammation in Mice fed a High-Fat Diet

Mice Deficient in the IL-1β Activation Genes Prtn3, Elane, and Casp1 Are Protected Against the Development of Obesity-Induced NAFLD

Metabo groups in response to micronutrient intervention: Pilot study

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