Title
Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration
Author
Wang, Y.
Parlevliet, E.T.
Geerling, J.J.
van der Tuin, S.J.L.
Zhang, H.
Bieghs, V.
Jawad, A.H.M.
Shiri-Sverdlov, R.
Bot, I.
de Jager, S.C.A.
Havekes, L.M.
Romijn, J.A.
Willems Van Dijk, K.
Rensen, P.C.N.
Publication year
2014
Abstract
Background and Purpose The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. Experimental Approach Female APOE 3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. Key Results Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68+ (-18%) and F4/80+ (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1+ macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. Conclusions and Implications Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously. © 2013 The British Pharmacological Society.
Subject
Life
MHR - Metabolic Health Research
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
Cholesterol
Exendin-4
Inflammation
Macrophage content
Monocyte recruitment
Oxidized LDL
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http://resolver.tudelft.nl/uuid:66d280fb-c4ab-4b80-8715-cce2da76f425
DOI
https://doi.org/10.1111/bph.12490
TNO identifier
488261
ISSN
0007-1188
Source
British Journal of Pharmacology, 171 (3), 723-734
Document type
article