Association between plasminogen activator inhibitor‐1 and severity of liver injury and cardiovascular risk in children with non‐alcoholic fatty liver disease

Jin, Ran; Krasinskas, Alyssa M.; Le, Ngoc-Anh; Jv, Konomi; Holzberg, Jeffrey R.; Romero, René; Mb, Vos

doi:10.1111/ijpo.12183

Cited by 24 publications

(19 citation statements)

References 30 publications

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“…In this regard, plasminogen activator inhibitor-1 (PAI-1) has been suggested as an early marker of metabolic health in obese children, 40 strongly related to lipids and insulin resistance. 41 It is therefore evident that obese children have a higher prevalence of CVD risk factors compared with normal weight peers. The clustering of risk factors in obese children is detrimental to their health as these risk factors accumulate as the children grow into adulthood.…”

Section: Insulin Resistance and Diabetesmentioning

confidence: 99%

Risk factors and predictive biomarkers of early cardiovascular disease in obese youth

Maddaloni

Buzzetti

2019

Diabetes Metabolism Res

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Obesity in childhood and adolescence continues to be a major health issue due to significant health implications and to the economic burden that arise from treating this disease and its complications. Current data show that childhood obesity is no longer just a concern for developed countries, but more significantly affecting developing countries. In adult population, cardiovascular disease is the main cause of mortality and morbidity among obese patients. It is therefore believed that risk factors found in adult patients could also be observed in obese youth. These risk factors will then persist and become progressively worse if obese youth remain obese as they reach adulthood. However, risk reduction is achievable through various prevention and management strategies of obesity and obese children who become nonobese in adulthood have a significant reduction in their risk of developing cardiovascular disease.New biomarkers to improve risk assessment in obese youth are an open research field, which will eventually lead to a more targeted approach in prevention and treatment. Nevertheless, there is still a need for continuous research in understanding the roles of these biomarkers and their potential in risk prediction. Cardiovascular risk modification of childhood obesity depends on a more concerted effort among the various parties involved and particularly a global collaboration to stop the rising prevalence of the epidemic in developing countries.

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Section: Insulin Resistance and Diabetesmentioning

confidence: 99%

Risk factors and predictive biomarkers of early cardiovascular disease in obese youth

Maddaloni

Buzzetti

2019

Diabetes Metabolism Res

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“…Plasminogen activator inhibitor-1 (PAI-1) is an acute-phase protein which increases in states of insulin resistance, inflammation, and injury [ 8 ] and is elevated in both adults and children with hepatic steatosis [ 9 – 11 ]. Furthermore, PAI-1 correlates with fibrosis stage [ 12 , 13 ]. The renin-angiotensin system (RAS) has been suggested to be involved in liver damage pathways and might play a critical role in the pathogenesis of NAFLD [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease

Vos

Jin

Konomi

et al. 2018

Pilot Feasibility Stud

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BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children, and currently, there are no FDA-approved therapies. Plasminogen activator inhibitor-1 (PAI-1) is elevated in children with NAFLD and associated with increased disease severity. Losartan potassium (losartan) is an angiotensin II receptor blocker (ARB) that reduces PAI-1 production and improves insulin sensitivity that has been proposed as a treatment for pediatric NAFLD but has not previously been tested.MethodsThis was an 8-week randomized, double-blind, placebo-controlled, phase 2a, crossover study (with a 6-week washout between conditions) for safety and preliminary efficacy of losartan 50 mg a day taken orally in 12 normotensive children with biopsy proven nonalcoholic steatohepatitis (NASH).ResultsTwelve children enrolled in the study, and nine completed all visits. No changes in blood pressure or serious adverse events occurred during the study. Trends in improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and homeostatic model assessment insulin resistance (HOMA-IR) were seen with losartan treatment compared to the placebo time-period. More participants decreased ALT on losartan as compared to placebo (89% [8 out 9] vs. 56% [5 out of 9], respectively).ConclusionsThis data provides preliminary evidence that losartan treatment is safe over 8 weeks in children with NAFLD and supports consideration of larger studies to test its efficacy.Trial registrationURL and trial identification number: https://clinicaltrials.gov/show/NCT01913470, NCT01913470.Date registered: August 1, 2013.

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“…The Serpine1 named also PAI-1 plays a key role as inhibitor of fibrinolysis and important roles in inflammation and wound healing. Over-expression of PAI-1 has been related to diabetes and metabolic syndrome features, while hepatic over-expression of PAI-1 has been coassociated with NAFLD severity/type and insulin resistance (Jin et al 2018), which implies the potential targeting of hepatic PAI-1 as a possible marker for diabetic/metabolic syndrome progress. Interestingly, in this context, a study of human hepatic gene expression in health versus diabetes has reported down-regulation of plasminogen in diabetic subjects (Takamura et al 2004).…”

Section: De Genes Of the Inflammatory Systemmentioning

confidence: 99%

Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population

et al. 2019

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Hepatic gene expression is known to differ between healthy and type 2 diabetes conditions. Identifying these variations will provide better knowledge to the development of gene-targeted therapies. The aim of this study is to assess diet-induced hepatic gene expression of susceptible versus resistant CC lines to T2D development. Next-generation RNA-sequencing was performed for 84 livers of diabetic and non-diabetic mice of 41 different CC lines (both sexes) following 12 weeks on high-fat diet (42% fat). Data analysis revealed significant variations of hepatic gene expression in diabetic versus non-diabetic mice with significant sex effect, where 601 genes were differentially expressed (DE) in overall population (males and females), 718 genes in female mice, and 599 genes in male mice. Top prioritized DE candidate genes were Lepr, Ins2, Mb, Ckm, Mrap2, and Ckmt2 for the overall population; for females-only group were Hdc, Serpina12, Socs1, Socs2, and Mb, while for males-only group were Serpine1, Mb, Ren1, Slc4a1, and Atp2a1. Data analysis for sex differences revealed 193 DE genes in health (Top: Lepr, Cav1, Socs2, Abcg2, and Col5a3), and 389 genes DE between diabetic females versus males (Top: Lepr, Clps, Ins2, Cav1, and Mrap2). Furthermore, integrating gene expression results with previously published QTL, we identified significant variants mapped at chromosomes at positions 36-49 Mb, 62-71 Mb, and 79-99 Mb, on chromosomes 9, 11, and 12, respectively. Our findings emphasize the complexity of T2D development and that significantly controlled by host complex genetic factors. As well, we demonstrate the significant sex differences between males and females during health and increasing to extent levels during disease/diabetes. Altogether, opening the venue for further studies targets the discovery of effective sex-specific and personalized preventions and therapies.

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Association between plasminogen activator inhibitor‐1 and severity of liver injury and cardiovascular risk in children with non‐alcoholic fatty liver disease

Cited by 24 publications

References 30 publications

Risk factors and predictive biomarkers of early cardiovascular disease in obese youth

Risk factors and predictive biomarkers of early cardiovascular disease in obese youth

A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease

Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population

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