Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, LV-1006 Riga, Latvia.
Faculty of Biology, University of Latvia, Jelgavas Str. 1, LV-1004 Riga, Latvia.
Int J Mol Sci. 2021 Jun 16;22(12):6470. doi: 10.3390/ijms22126470.
The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.
脂质中间体的积累可能会干扰能量代谢途径并调节细胞能量供应。由于长链酰基辅酶 A 的水平升高与胰岛素抵抗有关，我们研究了长链酰基辅酶 A 对胰岛素信号通路关键成分的影响。我们发现，棕榈酰基辅酶 A 通过增加蛋白酪氨酸磷酸酶 1B（PTP1B）的活性来诱导胰岛素受体（InsR）的去磷酸化。棕榈酰基辅酶 A 抑制蛋白激酶 B（Akt）在 Ser473 处的磷酸化，而胰岛素增敏剂双-（麦芽醇基）氧钒（IV）抑制 PTP1B 并不能缓解这种作用。这一结果表明，棕榈酰基辅酶 A 影响 Akt 活性独立于 InsR 磷酸化水平。抑制蛋白激酶 C 和蛋白磷酸酶 2A 并不影响棕榈酰基辅酶 A 介导的 Akt Ser473 磷酸化抑制。此外，棕榈酰基辅酶 A 通过抑制胰岛素分泌细胞 RIN5F 中的 Akt Ser473 磷酸化显著刺激胰岛素释放。总之，长链酰基辅酶 A 激活 PTP1B，降低 InsR Tyr1151 磷酸化和 Akt Ser473 磷酸化，从而限制细胞对胰岛素刺激的反应。
