Abstract
Accumulated evidence shows that G protein-coupled receptor 119 (GPR119) plays a key role in glucose and lipid metabolism. Here, we explored the effect of GPR119 on cholesterol metabolism and inflammation in THP-1 macrophages and atherosclerotic plaque progression in apoE(-/-) mice. We found that oxidized LDL (Ox-LDL) significantly induced long intervening noncoding RNA (lincRNA)-DYNLRB2-2 expression, resulting in the upregulation of GPR119 and ABCA1 expression through the glucagon-like peptide 1 receptor signaling pathway. GPR119 significantly decreased cellular cholesterol content and increased apoA-I-mediated cholesterol efflux in THP-1 macrophage-derived foam cells. In vivo, apoE(-/-) mice were randomly divided into two groups and infected with lentivirus (LV)-Mock or LV-GPR119 for 8 weeks. GPR119-treated mice showed decreased liver lipid content and plasma TG, interleukin (IL)-1β, IL-6, and TNF-α levels, whereas plasma levels of apoA-I were significantly increased. Consistent with this, atherosclerotic lesion development was significantly inhibited by infection of apoE(-/-) mice with LV-GPR119. Our findings clearly indicate that, Ox-LDL significantly induced lincRNA-DYNLRB2-2 expression, which promoted ABCA1-mediated cholesterol efflux and inhibited inflammation through GPR119 in THP-1 macrophage-derived foam cells. Moreover, GPR119 decreased lipid and serum inflammatory cytokine levels, decreasing atherosclerosis in apoE(-/-) mice. These suggest that GPR119 may be a promising candidate as a therapeutic agent.
Highlights
Accumulated evidence shows that G protein-coupled receptor 119 (GPR119) plays a key role in glucose and lipid metabolism
Monocytes are recruited from the circulation into the subendothelial space, where they differentiate into mature macrophages and internalize modified lipoproteins to differentiate into lipid-laden foam cells [25]
The results showed that long intervening noncoding RNA (lincRNA)-DYNLRB2-2 (BM973870; 16q23.3, chr16:79,831,946-79,861,047) expression was upregulated in THP-1 macrophage-derived foam cells (4.688-fold, P < 0.001), suggesting that oxidized LDL (Ox-LDL) and
Summary
Accumulated evidence shows that G protein-coupled receptor 119 (GPR119) plays a key role in glucose and lipid metabolism. GPR119 significantly decreased cellular cholesterol content and increased apoA-I-mediated cholesterol efflux in THP-1 macrophage-derived foam cells. Our findings clearly indicate that, Ox-LDL significantly induced lincRNA-DYNLRB2-2 expression, which promoted ABCA1-mediated cholesterol efflux and inhibited inflammation through GPR119 in THP-1 macrophage-derived foam cells. ABCA1 is a member of a family of highly conserved transmembrane transport proteins It plays a crucial role in the efflux of cellular cholesterol to HDL and its apolipoproteins [3]. G protein-coupled receptor 119 (GPR119), which has been described as a deorphanized G protein-coupled receptor, plays a significant role in mediating systemic metabolic homeostasis It has recently attracted attention because evidence from in vitro systems and animal models suggests that its modulation has a favorable effect on glucose homoeostasis [5, 6].
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