Fatty acid (FA) signaling contributes to β-cell mass expansion in response to nutrient excess, but the underlying mechanisms are poorly understood. In the presence of elevated glucose, FA metabolism is shifted toward synthesis of complex lipids, including sphingolipids. Here, we tested the hypothesis that sphingolipids are involved in the β-cell proliferative response to FA. Isolated rat islets were exposed to FA and 16.7 mmol/L glucose for 48–72 h, and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or knockdown of SphK, fatty acid elongase 1 (ELOVL1) and acyl-CoA–binding protein (ACBP). Rats were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. β-Cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipids were analyzed by liquid chromatography-tandem mass spectrometry. Among the FAs tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced β-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced β-cell proliferation. We conclude that unsaturated very-long-chain sphingolipids produced from the available C24:1 acyl-CoA pool mediate oleate-induced β-cell proliferation in rats.

中文翻译：

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超长链不饱和鞘脂介导油酸盐诱导的大鼠 β 细胞增殖

脂肪酸 (FA) 信号有助于 β 细胞大量扩增以响应营养过剩，但其潜在机制知之甚少。在葡萄糖升高的情况下，FA 代谢转向合成复杂脂质，包括鞘脂。在这里，我们检验了鞘脂参与 FA 的 β 细胞增殖反应的假设。将分离的大鼠胰岛暴露于 FA 和 16.7 mmol/L 葡萄糖 48-72 小时，并使用丝氨酸棕榈酰转移酶抑制剂多球菌素、鞘氨醇激酶 (SphK) 抑制剂 SKI II 或敲低测试鞘脂从头合成途径的贡献SphK、脂肪酸延长酶 1 (ELOVL1) 和酰基辅酶 A 结合蛋白 (ACBP)。给大鼠输注葡萄糖和脂肪乳剂 ClinOleic，并通过强饲法接受 SKI II。通过免疫化学或流式细胞术评估 β 细胞增殖。通过液相色谱-串联质谱分析鞘脂。在测试的 FAs 中，只有油酸盐增加了 β 细胞增殖。Myriocin、SKI II 和 SphK 敲除均降低了油酸盐诱导的 β 细胞增殖。油酸盐暴露不会增加鞘脂的总量，但会导致 24:1 物种的特定增加。ACBP 或 ELOVL1 的敲低抑制了油酸盐诱导的 β 细胞增殖。我们得出结论，由可用的 C24:1 酰基辅酶 A 池产生的不饱和超长链鞘脂介导大鼠中油酸盐诱导的 β 细胞增殖。和 SphK 敲低均降低了油酸盐诱导的 β 细胞增殖。油酸盐暴露不会增加鞘脂的总量，但会导致 24:1 物种的特定增加。ACBP 或 ELOVL1 的敲低抑制了油酸盐诱导的 β 细胞增殖。我们得出结论，由可用的 C24:1 酰基辅酶 A 池产生的不饱和超长链鞘脂介导大鼠中油酸盐诱导的 β 细胞增殖。和 SphK 敲低均降低了油酸盐诱导的 β 细胞增殖。油酸盐暴露不会增加鞘脂的总量，但会导致 24:1 物种的特定增加。ACBP 或 ELOVL1 的敲低抑制了油酸盐诱导的 β 细胞增殖。我们得出结论，由可用的 C24:1 酰基辅酶 A 池产生的不饱和超长链鞘脂介导大鼠中油酸盐诱导的 β 细胞增殖。