Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non‐alcoholic fatty liver disease

Munsterman, Isabelle D.; Kendall, Timothy J.; Khelil, Nawel; Popa, Mădălina; Lomme, Roger M. L. M.; Drenth, Joost P.H.; Tjwa, Eric T.

doi:10.1111/his.13665

Cited by 36 publications

(30 citation statements)

References 35 publications

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“…MMPs play a crucial role in ECM homeostasis due to HSC activation into a profibrogenic phenotype occurring during inflammation [37,38]. Recent data have shown an ongoing remodelling activity of MMP-2 in advanced human NAFLD fibrosis [39]. In the present study, we documented, for the first time, a positive correlation between desaturases, D5D, D9-16D and D19-18D, with MMP-2 protein content and its gelatinolytic activity in NAFLD animal models.…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Palladini

Pasqua²,

Berardo³

et al. 2019

Nutrients

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We investigated changes in fatty acid desaturases, D5D, D6D, D9-16D and D9-18D, and their relationship with oxidative stress, matrix metalloproteinases (MMPs) and serum TNF-alpha in two rat models of non-alcoholic fatty liver disease NAFLD. Eight-week-old male Wistar rats fed for 3 weeks with methionine-choline–deficient (MCD) diet and eleven-week-old Obese male Zucker rats were used. Serum levels of hepatic enzymes and TNF-alpha were quantified. Hepatic oxidative stress (ROS, TBARS and GSH content) and MMP-2 and MMP-9 (protein expression and activity) were evaluated. Liver fatty acid profiling, performed by GC-MS, was used for the quantification of desaturase activities. Higher D5D and D9-16D were found in Obese Zucker rats as well as an increase in D9-18D in MCD rats. D6D was found only in MCD rats. A negative correlation between D5D and D9-16D versus TBARS, ROS and TNF-alpha and a positive correlation with GSH were shown in fatty livers besides a positive correlation between D9-18D versus TBARS, ROS and TNF-alpha and a negative correlation with GSH. A positive correlation between D5D or D9-16D or D9-18D versus protein expression and the activity of MMP-2 were found. NAFLD animal models showed comparable serum enzymes. These results reinforce and extend findings on the identification of therapeutic targets able to counteract NAFLD disorder.

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Section: Discussionmentioning

confidence: 99%

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Palladini

Pasqua²,

Berardo³

et al. 2019

Nutrients

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“…Furthermore, to explore the relation between PR3, NE and AAT and the advanced stages of NAFLD we selected a cohort of 41 patients with biopsy-diagnosed NAFLD. Patients included in this cohort were recruited in the context of another clinical study regarding development of fibrosis in NAFLD and patients’ characteristics were previously described (Munsterman et al 2018).…”

Section: Methodsmentioning

confidence: 99%

“…Liver lysates were prepared as previously described (Munsterman et al 2018). PR3 and NE concentrations were measured in liver lysates according to manufacter’s protocol (cat# HK384, HK319 respectively, Hycult Biotech, Uden, The Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Increased proteinase 3 and neutrophil elastase plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes

Mirea

Toonen

Munckhof

et al. 2019

Mol Med

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Introduction Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes. Methods To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls. Results Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls. Conclusion We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes. Electronic supplementary material The online version of this article (10.1186/s10020-019-0084-3) contains supplementary material, which is available to authorized users.

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“…In accordance, Hemman et al [50] previously reported that in activated HSCs, TIMP-1 expression is increased, and concomitantly MMPs activity is reduced, leading to protein accumulation. Recently, an increase of pro-MMP-2 accompanied by increased TIMP-1 and TIMP-2 levels in NAFLD liver fibrosis [51] has been reported. In accordance, Yilmaz et al [52] described an increase of TIMP-1 serum levels in patients with significant fibrosis, and this was identified as an independent predictor of histological fibrosis.…”

Section: The Role Of Mmps In Different Tissuesmentioning

confidence: 99%

Behavior of Metalloproteinases in Adipose Tissue, Liver and Arterial Wall: An Update of Extracellular Matrix Remodeling

Berg

Barchuk

Miksztowicz

2019

Cells

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Extracellular matrix (ECM) remodeling is required for many physiological and pathological processes. Metalloproteinases (MMPs) are endopeptidases which are able to degrade different components of the ECM and nucleus matrix and to cleave numerous non-ECM proteins. Among pathological processes, MMPs are involved in adipose tissue expansion, liver fibrosis, and atherosclerotic plaque development and vulnerability. The expression and the activity of these enzymes are regulated by different hormones and growth factors, such as insulin, leptin, and adiponectin. The controversial results reported up to this moment regarding MMPs behavior in ECM biology could be consequence of the different expression patterns among species and the stage of the studied pathology. The aim of the present review was to update the knowledge of the role of MMPs and its inhibitors in ECM remodeling in high incidence pathologies such as obesity, liver fibrosis, and cardiovascular disease.

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Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non‐alcoholic fatty liver disease

Abstract: Advanced human NAFLD-fibrosis has a distinct ECM composition with increased HSCs and increased TIMP inhibition, but there is also ongoing remodelling activity of MMP-2.

Cited by 36 publications

References 35 publications

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Increased proteinase 3 and neutrophil elastase plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes

Behavior of Metalloproteinases in Adipose Tissue, Liver and Arterial Wall: An Update of Extracellular Matrix Remodeling

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