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

Y. Wang, E.T. Parlevliet, J.J. Geerling, S.J. van der Tuin, H. Zhang, V. Bieghs, A.H. Jawad, R. Shiri-Sverdlov, I. Bot, S.C. de Jager, L.M. Havekes, J.A. Romijn, K van Dijk, P.C. Rensen

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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.
Original languageEnglish
Pages (from-to)723-734
Number of pages12
JournalBritish Journal of Pharmacology
Volume171
Issue number3
DOIs
Publication statusPublished - Feb 2014

Keywords

  • cholesterol
  • exendin-4
  • inflammation
  • macrophage content
  • monocyte recruitment
  • oxidized LDL
  • TYPE-2 DIABETES-MELLITUS
  • GLP-1 RECEPTOR AGONIST
  • NONALCOHOLIC STEATOHEPATITIS
  • HEPATIC STEATOSIS
  • ARRIVE GUIDELINES
  • TRANSGENIC MICE
  • DISEASE
  • LIRAGLUTIDE
  • PROGRESSION
  • ACTIVATION

Cite this

Wang, Y., Parlevliet, E. T., Geerling, J. J., van der Tuin, S. J., Zhang, H., Bieghs, V., Jawad, A. H., Shiri-Sverdlov, R., Bot, I., de Jager, S. C., Havekes, L. M., Romijn, J. A., van Dijk, K., & Rensen, P. C. (2014). Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. British Journal of Pharmacology, 171(3), 723-734. https://doi.org/10.1111/bph.12490