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  • Our previous study had shown that silencing

    2022-01-14

    Our previous study had shown that silencing FFAR1 expression weakened the action of PIO in increasing insulin secretion in lipotoxic β Tranexamic Acid [6]. Resent research found that PIO promoted insulin secretion by upregulating FFAR1 [17]. Therefore, we presumed that FFAR1 may be involved in the anti-lipoapoptosis effect of PIO. We confirmed our hypothesis with the following three results. Firstly, we observed that PIO enhanced FFAR1 expression in lipotoxic β cells in a dose- and time-dependent manner. Secondly, we found that silencing FFAR1 expression prevented the anti-lipoapoptosis effect of PIO; conversely, inducing FFAR1 overexpression enhanced the protecting action of PIO. Lastly, we found the levels of FFAR1 expression were negatively correlated with β-cell apoptosis. These aforementioned results showed that FFAR1 is involved in the protective action of PIO, which suggested FFAR1 attenuates β-cell lipotoxicity damage. Recent studies have also supported our results. Clinical pathology studies have found lower levels of FFAR1 expression in the β cells of patients with diabetes [18]. Cytological studies have shown that unsaturated fatty acids protect β cells from glucose toxicity and lipotoxicity by activating FFAR1 expression [19]. In diabetic animal models, administration of a FFAR1 agonist appeared to increase insulin secretion and lower blood glucose levels [20], [21]. Our results showed that PIO treatment slightly increased the mRNA and protein level of FFAR1, but the difference was not statistically significant between the control group and PIO treatment group. PIO treatment can reverse the suppression of FFAR1 by PA. The underlying reasons are yet to be identified. There was a significant association between oxidative stress and conventional risk factors in the metabolic syndrome [22]. It is known that NADPH oxidase in the ROS system mediates FFAs-induced β-cell damage [23]. Studies have shown that PPARγ agonists prevent oxidative stress by inhibiting NADPH oxydase activation and decreasing ROS production [24], [25]. Therefore, this study further investigated whether FFAR1 mediated its effect through an anti-oxidative stress manner. Our results showed that PIO inhibited the increasing expression of NADPH oxydase, Bax, and ROS, and upregulated bcl-2 expression in lipotoxic β cells. The restoring effect of PIO was inhibited when FFAR1 expression was silenced, but was enhanced when FFAR1 overexpression was induced. Similarly, the mediating effect of FFAR1 on PIO was also found under the condition of H2O2-induced oxidative stress. Our results suggested that the mediating role of FFAR1 on PIO action was associated with anti-oxidative stress. The mechanism underlying the signaling pathway involved in FFAR1-mediated anti-lipotoxicity in β cells remains to be elucidated. It has been reported that FFAR1 increases insulin secretion through the PLC-IP3 signaling pathway [26], [27]. However, the downstream target of the PLC-IP3 pathway and whether it mediates other biological functions of FFAR1 remain unclear. Recent research has showed that silencing PLCβ1 and PLCδ4 expression in β cells downregulates PPARγ expression, and thus, affects β-cell insulin secretion [28]. The activation of FFAR1 was found to upregulate PPARδ expression and compensated for insulin resistance in hepatocytes [29]. PLC was found to activate the Raf-MEK-ERK pathway and phosphorylated ERK to activate PPARγ. Studies have also shown that FFA induced cell apoptosis by inhibiting ERK phosphorylation [30]. These studies have suggested that PPARγ may be the downstream target protein of the FFAR1-PLC pathway. Therefore, our study further analyzed whether the mechanism underlying the effect FFAR1 involves PLCγ-ERK1/2-PPARγ signaling. Our results showed that both PIO and TAK-875, a specific agonist of FFAR1, upregulated the expression of PLCγ, ERK1/2, and PPARγ in lipotoxic β cells, while silencing FFAR1 expression prevented the protective effect of PIO on PLCγ, ERK1/2, and PPARγ expression in lipotoxic β cells, and inducing FFAR1 overexpression enhanced the protective action of PIO. In addition, inhibiting PLCγ, ERK1/2, or PPARγ activity was found to reduce the protective of effect PIO on oxidative stress and lipoapoptosis in β cells. The aforementioned results suggest that the effect of PIO and FFAR1 is associated with PLCγ-ERK1/2-PPARγ pathway activation.