Exendin‐4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. (February 2014)

• Record Type: Journal Article
• Authors: Wang, Y; Parlevliet, E T; Geerling, J J; van der, S J L; Zhang, H; Bieghs, V; Jawad, A H M; Shiri‐Sverdlov, R; Bot, I; de, S C A; Havekes, L M; Romijn, J A; Willems van Dijk, K; Rensen, P C N
• Is Part Of: British journal of pharmacology. Volume 171:Number 3(2014:Feb.)
• Page Start: 723
• Page End: 734
• Publication Date: 2014-02
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12490
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12490-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12490-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Female <italic>APOE*3‐Leiden.CETP</italic> 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.</p> </sec> <sec id="bph12490-sec-0003" sec-type="section"> <title>Key Results</title> <p>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<sup>+</sup> (−18%) and F4/80<sup>+</sup> (−25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac‐1<sup>+</sup> macrophage content was decreased (−36%). Finally, exendin‐4 reduced hepatic chemokine expression <italic>in vivo</italic> and suppressed oxidized low‐density lipoprotein accumulation in peritoneal macrophages <italic>in vitro</italic>, effects dependent on the GLP‐1 receptor.</p> </sec> <sec id="bph12490-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>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.</p> </sec> </abstract>