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


METHODS
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.


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
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.
Department 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.
Y
Y
Wang
E T
ET
Parlevliet
J J
JJ
Geerling
S J L
SJ
van der Tuin
H
H
Zhang
V
V
Bieghs
A H M
AH
Jawad
R
R
Shiri-Sverdlov
I
I
Bot
S C A
SC
de Jager
L M
LM
Havekes
J A
JA
Romijn
K
K
Willems van Dijk
P C N
PC
Rensen
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic / Q000009:adverse effects; D004195:Disease Models, Animal; D004343:Drug Implants; D050171:Dyslipidemias / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000077270:Exenatide; D005234:Fatty Liver / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use; D011897:Random Allocation; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053318:Apolipoprotein E3; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004343:Drug Implants; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D000960:Hypolipidemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide
cholesterol; exendin-4; inflammation; macrophage content; monocyte recruitment; oxidized LDL