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    • In this study we describe the role of

    2022-04-20

    In this study, we describe the role of a specific species of LPI in the secretion of GLP-1 from enteroendocrine L-cells and primary cell preparations. We further demonstrate the specific role of GPR119 in LPI-dependent GLP-1 secretion. To achieve this, we downregulated GPR119 and GPR55 protein expression in vitro through specific siRNAs and we used colonic primary preparations from GPR55−/− and GPR119−/− transgenic mouse models in ex vivo experiments. Investigation of the Oleoyl-LPI-induced GLP-1 secretion mechanism revealed that GPR119 activation regulates GLP-1 secretion through a pathway dependent on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and stimulation of a cAMP/protein kinase A (PKA)-dependent pathway.
    Materials and methods
    Results
    Discussion It has been reported that both pancreas and gastrointestinal tract express high levels of GPR55, and GPR119. Recently, the lysophospholipid LPI was identified as a ligand for GPR55 and we hypothesized that GPR119 could be another potential LPI receptor. For instance, it has been reported that LPI can activate GPR119 in RH7777 rat hepatoma inhibitor of apoptosis proteins stably expressing human GPR119 [11]. Activation of GPR119 in the pancreas is correlated with enhanced glucose stimulated insulin secretion and activation of this receptor in the gut results in increased secretion of incretin hormones GLP-1 and GIP [4, 38]. These observations suggest that GPR119 activation may reduce blood glucose levels by acting on L-cells to stimulate GLP-1 release that in turn stimulate β-cells to promote glucose stimulated insulin secretion. Therefore, activation of this receptor by Oleoyl-LPI could be an interesting therapeutic target for treatment of T2D. The overall aim of this study was to explore the potential role of LPI in the secretion of GLP-1 by enteroendocrine L-cells through the activation of GPR119, and the mechanism underlying this process. Our study demonstrated that Oleoyl-LPI increases GLP-1 secretion in-vitro and in ex-vivo preparations of enteroendocrine L-cells. Previous reports have demonstrated that fatty acids containing an oleoyl chain such as Oleoylethanolamide (OEA) and 2-Oleoyl-glycerol (2-OG) can enhance secretion of GLP-1 by enteroendocrine cells [4, 20]. Oleoyl-LPI is an endogenous phospholipid with an inositol head and an acylated Oleoyl chain (18:1). A heterogeneous mixture of different species of LPI, with distinct acyl chains, primarily saturated, was initially described as the endogenous ligand for GPR55 [18]. This LPI-GPR55 binding, similarly to multiple cannabinoids, is reported to activate a downstream Gα13/RhoA/ROCK-dependent calcium signalling [39]. More recently, the presence of the cation channel TRPV2 was found to be necessary for the activation of this pathway [40]. Nonetheless, the stimulation of GPR55 with the synthetic agonist O-1605, fails to mimic the reported LPI activity, indicating the involvement of other molecular players. Indeed, the data reported by the authors, clearly indicate only a minor involvement of GPR55 in the LPI-mediated secretion of GLP-1, and fail to address the composition of the LPI mixture [40]. Another interesting finding that we report is that Oleoyl-LPI displays a much higher GLP-1 secreting activity than OEA (Fig. 1D and E), despite similar cAMP raising capabilities (Fig. S3). These data appeared to be in contrast with those of Lauffer et al. [20] which concluded that OEA induced GLP-1 secretion when tested at the same concentration (10 μM). Noticeably, these authors maintained the GLUTag cells culture in a higher glucose concentration of 25 mM and not at a level (5.5 mM) normally used for this cell line [25, 35, 37, 41, 42] therefore the possible interference of high glucose cannot be ruled out. A recent study [43] revealed that GLUTag cells cultured in high glucose concentration had increased total production and release of active GLP-1, reactive oxygen species and upregulated proglucagon mRNA expression. Our data further demonstrated that GPR119 is required for the Oleoyl-LPI-mediated GLP-1 secretion (Fig. 3).