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Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage
Y Wang1, E T Parlevliet, J J Geerling
1Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Insights
Exendin-4 reduces liver and vessel wall inflammation by decreasing macrophage recruitment and activation. This suggests exendin-4 as a potential treatment for non-alcoholic steatohepatitis (NASH) and atherosclerosis.
Area of Science:
- Cardiovascular Research
- Hepatology
- Immunology
Background:
- Non-alcoholic steatohepatitis (NASH) and atherosclerosis share inflammatory mechanisms, primarily macrophage infiltration.
- Targeting shared inflammatory pathways is crucial for treating both conditions concurrently.
- Exendin-4, a GLP-1 receptor agonist, is known to reduce hepatic steatosis and may impact atherosclerosis, but its anti-inflammatory effects in the liver require further investigation.
Purpose of the Study:
- To investigate the efficacy of exendin-4 in reducing inflammation in both the liver and vessel wall.
- To elucidate the common underlying mechanisms by which exendin-4 exerts its anti-inflammatory effects.
Main Methods:
- Female APOE*3-Leiden.CETP mice, a model for human-like lipoprotein metabolism, were fed a Western-type diet to induce atherosclerosis.
- Mice were subsequently treated with exendin-4 for four weeks to assess its therapeutic effects.
Main Results:
- Exendin-4 treatment significantly reduced atherosclerotic lesion severity and area by 33%, with decreased monocyte adhesion and macrophage content in plaques.
- Hepatic lipid content and inflammation were reduced, alongside decreased macrophage content (CD68+, F4/80+) and circulating monocyte recruitment (Mac-1+).
- Exendin-4 suppressed hepatic chemokine expression and oxidized LDL accumulation in macrophages, effects dependent on GLP-1 receptor activation.
Conclusions:
- Exendin-4 effectively reduces inflammation in both the liver and vessel wall by inhibiting macrophage recruitment and activation.
- These findings highlight exendin-4 as a promising therapeutic agent for simultaneously treating NASH and atherosclerosis.
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.
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