Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice

Busch, Clara Jana-Lui; Hendrikx, Tim; Weismann, David; Jäckel, Sven; Walenbergh, Sofie M. A.; Rendeiro, André F.; Weißer, Juliane; Puhm, Florian; Hladik, Anastasiya; Göderle, Laura; Papac-Miličević, Nikolina; Haas, G. G. de; Millischer, Vincent; Subramaniam, Saravanan; Knapp, Sylvia; Bennett, Keiryn L.; Bock, Christoph; Reinhardt, Carsten; Shiri-Sverdlov, Ronit; Binder, Christoph J.

doi:10.1002/hep.28970

Cited by 54 publications

(57 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to ER stress, oxidative stress and mitochondrial stress are able to initiate multiple inflammatory processes after excess fat accumulation in liver . Since high‐level resistin has a positive correlation with oxidative stress and inflammation, resistin may trigger steatosis progression into liver fibrogenesis via activating inflammatory processes .…”

Section: Discussionmentioning

confidence: 99%

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

Rong

Feng

Liu

et al. 2019

Journal of Pineal Research

View full text Add to dashboard Cite

Adipocyte‐derived exosomes (Exos) serve as bioinformation‐containing messengers in cell‐to‐cell communications, and numerous reports demonstrate that resistin, an adipokine, is strongly associated with hepatic steatosis and other fatty liver diseases, suggesting that adipose dysfunction‐generated altered pattern of exosomal cytokines may contribute to shaping the physiological activities in liver. Admittedly, melatonin‐mediated positive effects on various tissues/organs have been respectively reported, but regulatory mechanisms of melatonin on the crosstalk between adipose tissue and liver have been investigated rarely. Overall, we hypothesize that the crosstalk originating from adipose tissue may be another worthy regulatory pathway for melatonin ameliorating of hepatic steatosis. Here, we first found the amount of adipocyte‐derived exosomal resistin to be significantly decreased by melatonin supplementation. Compared to mice with ExosHFD or Exosresistin treatment, ExosMT remarkably ameliorated hepatic steatosis. Further test demonstrated that resistin was a pivotal cytokine which repressed phosphorylation of 5′ adenosine monophosphate‐activated protein kinase α (pAMPKα Thr172) to trigger endoplasmic reticulum (ER) stress, resulting in hepatic steatosis, whereas ExosMT reversed these risks in hepatocytes. In adipocytes, we identified melatonin to reduce the production of resistin through the brain and muscle arnt‐like protein 1 (Bmal1) transcriptional inhibition. Notably, we also confirmed that melatonin enhanced N6‐Methyladenosine (m6A) RNA demethylation to degrade resistin mRNA in adipocytes. Overall, melatonin decreases traffic volume of adipocyte‐generated exosomal resistin from adipocytes to hepatocytes, which further alleviates ER stress‐induced hepatic steatosis. Our findings illustrate a novel melatonin‐mediated regulatory pathway from adipocytes to hepatocytes, indicating that adipocyte‐derived exosome is a new potential target for treating obesity and related hepatorenal syndrome.

show abstract

Section: Discussionmentioning

confidence: 99%

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

Rong

Feng

Liu

et al. 2019

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…Indeed, MAA and oxidized phospholipid epitopes are enriched in nonalcoholic fatty liver disease and both alcoholic and nonalcoholic steatohepatitis (39–42). In that regard, the high and specific liver uptake of 89 Zr-LA25 may also allow imaging of the presence of OSEs in humans with these conditions.…”

Section: Discussionmentioning

confidence: 99%

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

Senders

Que

Cho

et al. 2018

Journal of the American College of Cardiology

View full text Add to dashboard Cite

BACKGROUND Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events. OBJECTIVES The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions. METHODS An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (89Zr)-labeled LA25. In rabbits, 89Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18F-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence. RESULTS LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of 89Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18F-fluorodeoxyglucose PET, dynamic contrast-enhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining. CONCLUSIONS 89Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions.

show abstract

“…In agreement with this view, by activation of the apoptotic Fas signaling pathway, hepatocyte apoptosis was demonstrated to play an important role in NASH. 75 Taking into consideration that oxidized lipids were previously found inside apoptotic cells, 76 oxLDL-induced hepatocyte apoptosis is a possible mechanism to trigger hepatic inflammation (Figure 2.2). Also, lipid peroxidation of F 2 -isoprostanes in hepatocytes mediated activation of stellate cells, thereby leading to hepatic fibrosis.…”

Section: Biological Evidence Linking Oxidized Lipids To Nashmentioning

confidence: 97%

“…75 In addition to their key role in intracellular digestion, increasing evidence assigns other important regulatory functions to lysosomes and associated enzymes. One of these regulatory functions is illustrated by the ability of the cell to discharge the lysosomal luminal content extracellularly (also termed extracellular vesicles (EVs)), 76 thereby regulating bone resorption, 77 hormonal homeostasis, 78 energy metabolism 79 and plasma membrane repair. 80 Relevantly, lysosomal exocytosis is also presumed as a mechanism to prevent the accumulation of intracellular debris (= to serve as protective physiological mechanism).…”

Section: Lysosomal Function and Its Role In Lipid Metabolism And Inflmentioning

confidence: 99%

“…High fat diet-induced changes in gut microbiota have been associated with metabolic syndrome-associated pathologies such as atherosclerosis, 72,73 NAFLD/NASH, 65 insulin resistance 74 and adipose tissue dysfunction. 65,75 However, malondialdehyde (which is a lipid peroxidation product contained inside oxLDL particles)-induced hepatic inflammation was independent of gut microbiota composition, 76 questioning the mechanistic role of gut microbiota to hepatic inflammation in this particular model. Other studies found associations between oxidized lipids and NASH development, 77,78 but none of these studies could mechanistically prove causality for the gut microbiome leading to hepatic inflammation.…”

mentioning

confidence: 96%

See 1 more Smart Citation

Lysosomes ‘in control’

Houben

View full text Add to dashboard Cite

Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice

Abstract: Accumulation of MDA epitopes plays a major role during diet-induced hepatic inflammation and can be ameliorated by administration of an anti-MDA antibody. (Hepatology 2017;65:1181-1195).

Cited by 54 publications

References 47 publications

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

Lysosomes ‘in control’

Contact Info

Product

Resources

About