Differential effects of GLP-1 receptor agonist on foam cell formation in monocytes between non-obese and obese subjects

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• 作者：Masashi Tanaka^a ; Yoshiyuki Matsuo^a ; Hajime Yamakage^a ; Shinya Masuda^a ; Yuko Terada^a ; Kazuya Muranaka^a ; Hiromichi Wada^b ; Koji Hasegawa^b ; Akira Shimatsu^a ; Noriko Satoh-Asahara^a ; ^{nsatoh@kuhp.kyoto-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AGEs ; advanced glycation end products ; DPP-4 ; dipeptidyl peptidase-4 ; Ex-4 ; exendin-4 ; GLP-1 ; glucagon-like peptide-1 ; GLP-1R ; GLP-1 receptor ; LC3 ; microtubule-associated protein 1 light chain 3 ; Mϕ ; macrophages ; NF-κB ; muclear factor-κB ; Ox-LDL ; oxidized-LDL ; PKA ; protein kinase A ; TLR ; Toll-like receptor
• 刊名：Metabolism
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：65
• 期：2
• 页码：1-11
• 全文大小：663 K

文摘

Monocytes/macrophages (Mϕ) transform into foam cells in the presence of oxidized-LDL (ox-LDL), releasing inflammatory mediators. The antiatherogenic role of a dipeptidyl peptidase-4 inhibitor is mediated, in part, through improving the unbalance of inflammatory (M1)/anti-inflammatory (M2) phenotypes in monocytes. In this study, we examined differential regulation of glucagon-like peptide-1 receptor (GLP-1R) signaling for antiatherogenesis in monocytes/Mϕ from normal-weight control subjects and obese patients.

Methods

We evaluated the effects of exendin-4 (Ex-4), a GLP-1R agonist, on ox-LDL-stimulated foam cell formation, M1/M2 cytokine production, and organelle change in primary monocytes from control subjects and obese patients and human monocytic THP-1-derived Mϕ as well.

Results

Here we report that Ex-4 suppressed foam cell formation and M1 cytokine expression and, interestingly, induced indicators of autophagy in ox-LDL-stimulated monocytes from control subjects. The suppressing effects on foam cell formation by Ex-4 were reversed by a cAMP inhibitor. In contrast to control subjects, Ex-4 did not induce indicators of autophagy, but did induce foam cell formation and M1 cytokine expression in monocytes from obese patients. GLP-1R expression level was comparable between control subjects and obese patients. The effects of Ex-4 on inducing indicators of autophagy and suppressing foam cell formation were observed in THP-1 Mϕ.

Conclusions

These data suggest that GLP-1R signaling induces autophagy, thereby suppressing foam cell formation in non-obese subjects. In obese patients, GLP-1R stimulation increased foam cell formation and IL-6, TNF-α, and IL-1β production. Such altered signaling in monocytes of obese patients may be involved in the development of atherosclerosis.