Serum Activity of Macrophage-Derived Adenosine Deaminase 2 Is Associated With Liver Fibrosis in Nonalcoholic Fatty Liver Disease

Jiang, Z. Gordon; Sandhu, Bynvant; Feldbrügge, Linda; Yee, Eric U.; Csizmadia, Eva; Mitsuhashi, Shuji; Huang, Jinhe; Afdhal, Nezam H.; Robson, Simon C.; Lai, Michelle

doi:10.1016/j.cgh.2017.11.028

Cited by 11 publications

(12 citation statements)

References 9 publications

(9 reference statements)

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“…Interestingly, metabolites from the purine metabolism pathway, namely inosine, guanosine, xanthosine, and urate, were elevated ( Figure 6L , Figure 6—figure supplement 1 ). This is particularly intriguing because adenosine deaminase (ADA), the enzyme that catalyzes the conversion of adenosine to inosine, is known to be more active in type 2 diabetic patients ( Kurtul et al, 2004 ) and is associated with liver fibrosis in NAFLD ( Jiang et al, 2018 ). Increases in ADA activity can lead to an increased flux through the purine metabolic pathway, eventually leading to increased production of urate by xanthine dehydrogenase (XDH) as the final step in the pathway ( Mandal and Mount, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Cadez

Zafer

et al. 2020

eLife

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Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.

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Section: Resultsmentioning

confidence: 99%

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Cadez

Zafer

et al. 2020

eLife

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“…Our observations suggest that infiltrative monocytes are the primary source of ADA2 in the extracellular milieu of the liver in humans. We identified a distinct population of portal macrophages that are both CD68 positive and ADA2 high, and are strongly correlated with liver fibrosis in NAFLD ( Jiang et al, 2018 ). These cells are distinguishable from Kupffer cells by their tissue distribution, cell morphology, and cellular biomarkers.…”

Section: Discussionmentioning

confidence: 96%

“…Patients with type 2 diabetes, a condition often co-existing with NAFLD, can also have an increase in circulating ADA2 activity ( Larijani et al, 2016 ). We have previously shown that high serum ADA2 activity is associated with increased stages of liver fibrosis in NAFLD ( Jiang et al, 2018 ). In vitro , ADA2-stimulated macrophages demonstrate both pro-inflammatory and pro-fibrotic characteristics, a phenotype resembling M2b class, including the simultaneous upregulation of IL1, IL6, IL10, TNFα, and downregulation of CD163.…”

Section: Discussionmentioning

confidence: 99%

“…The upregulation of PDGF-B has been reported in tumor-associated macrophages (TAM) to promote stroma formation ( Vignaud et al, 1994 ). The median serum ADA2 activity in NAFLD is about 5 U/L, while patients with advanced fibrosis had serum ADA2 activities reaching 10–20 U/L ( Jiang et al, 2018 ). In our experiments, extracellular ADA2 at 100 nM (84 U/L), significantly augmented PDGF-B production, while 10 nM ADA2 (8.4 U/L) may also have a detectable impact ( Figure 3F ) ( Vignaud et al, 1994 ).…”

Section: Discussionmentioning

confidence: 99%

“…In the human liver, CD39 (ENTPD1) was found in endothelial and immune cells, ENTPD8 in hepatocytes, and CD73 in hepatocytes and endothelial cells ( MacParland et al, 2018 ). Among the three enzymatic steps that convert ATP to inosine, the activity of the last deaminase step in the serum is robustly associated with liver fibrosis in NAFLD patients ( Jiang et al, 2018 ). Humans have two isoforms of ADA: ADA1 and ADA2.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease

et al. 2021

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Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD

Abdelhameed,

Kite,

Lagojda

et al. 2024

Curr Obes Rep

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Purpose of Review The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause of liver related morbidity and mortality. Currently, liver biopsy is the gold standard for assessing individuals with steatohepatitis and fibrosis. However, its invasiveness, sampling variability, and impracticality for large-scale screening has driven the search for non-invasive methods for early diagnosis and staging. In this review, we comprehensively summarise the evidence on the diagnostic performance and limitations of existing non-invasive serum biomarkers and scores in the diagnosis and evaluation of steatosis, steatohepatitis, and fibrosis. Recent Findings Several non-invasive serum biomarkers and scores have been developed over the last decade, although none has successfully been able to replace liver biopsy. The introduction of new NAFLD terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has initiated a debate on the interchangeability of these terminologies. Indeed, there is a need for more research on the variability of the performance of non-invasive serum biomarkers and scores across the diagnostic entities of NAFLD, MAFLD and MASLD. Summary There remains a significant need for finding valid and reliable non-invasive methods for early diagnosis and assessment of steatohepatitis and fibrosis to facilitate prompt risk stratification and management to prevent disease progression and complications. Further exploration of the landscape of MASLD under the newly defined disease subtypes is warranted, with the need for more robust evidence to support the use of commonly used serum scores against the new MASLD criteria and validation of previously developed scores.

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Serum Activity of Macrophage-Derived Adenosine Deaminase 2 Is Associated With Liver Fibrosis in Nonalcoholic Fatty Liver Disease

Cited by 11 publications

References 9 publications

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease

Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD

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