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Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration

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Author: Wang, Y. · Parlevliet, E.T. · Geerling, J.J. · Tuin, S.J.L. van der · Zhang, H. · Bieghs, V. · Jawad, A.H.M. · Shiri-Sverdlov, R. · Bot, I. · Jager, S.C.A. de · Havekes, L.M. · Romijn, J.A. · Willems Van Dijk, K. · Rensen, P.C.N.
Source:British Journal of Pharmacology, 3, 171, 723-734
Identifier: 488261
doi: doi:10.1111/bph.12490
Keywords: Biology · Cholesterol · Exendin-4 · Inflammation · Macrophage content · Monocyte recruitment · Oxidized LDL · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences


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.