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 language | English |
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Pages (from-to) | 723-734 |
Number of pages | 12 |
Journal | British Journal of Pharmacology |
Volume | 171 |
Issue number | 3 |
DOIs | |
Publication status | Published - 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