Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway.
Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway.
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DOI：
10.1172/jci146219
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发表时间：
2022-04-01
期刊：
影响因子：
--
通讯作者：
Haeusler RA
中科院分区：
文献类型：
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作者：
Izquierdo MC;Shanmugarajah N;Lee SX;Kraakman MJ;Westerterp M;Kitamoto T;Harris M;Cook JR;Gusarova GA;Zhong K;Marbuary E;O-Sullivan I;Rasmus N;Camastra S;Unterman TG;Ferrannini E;Hurwitz BE;Haeusler RA
HDL的多种有益心血管作用取决于鞘氨醇-1-磷酸（S1 P）。S1 P通过与载脂蛋白M（ApoM）结合而与HDL结合。胰岛素抵抗是血脂异常和心血管风险的主要驱动因素。然而，胰岛素信号传导改变与血浆脂蛋白代谢之间的联系机制尚不完全清楚。胰岛素抑制性FoxO转录因子介导肝脏胰岛素作用对葡萄糖和脂蛋白代谢的关键作用。这项工作测试了肝脏胰岛素信号是否调节HDL-S1 P，并旨在确定潜在的分子机制。我们报告，胰岛素抵抗，非糖尿病个体HDL-S1 P水平下降，但血浆总S1 P没有变化。这也发生在胰岛素抵抗db/db小鼠中，其具有低ApoM和HDL组分中S1 P的特异性降低，总血浆S1 P水平无变化。使用缺乏肝FoxO（L-FoxO 1，3，4）的小鼠，我们发现肝FoxO是ApoM表达所必需的。总血浆S1 P水平与对照组相似，但HDL中几乎不存在S1 P，而在脂蛋白耗尽的血浆组分中增加。通过拯救L-FoxO 1，3，4小鼠中的ApoM，使该表型恢复正常。我们的研究结果表明，人类和小鼠的胰岛素抵抗与HDL相关的S1 P降低有关。我们的研究表明，肝脏FoxO转录因子是ApoM/S1 P通路的调节因子。
Multiple beneficial cardiovascular effects of HDL depend on sphingosine-1-phosphate (S1P). S1P associates with HDL by binding to apolipoprotein M (ApoM). Insulin resistance is a major driver of dyslipidemia and cardiovascular risk. However, the mechanisms linking alterations in insulin signaling with plasma lipoprotein metabolism are incompletely understood. The insulin-repressible FoxO transcription factors mediate key effects of hepatic insulin action on glucose and lipoprotein metabolism. This work tested whether hepatic insulin signaling regulates HDL-S1P and aimed to identify the underlying molecular mechanisms. We report that insulin-resistant, nondiabetic individuals had decreased HDL-S1P levels, but no change in total plasma S1P. This also occurred in insulin-resistant db/db mice, which had low ApoM and a specific reduction of S1P in the HDL fraction, with no change in total plasma S1P levels. Using mice lacking hepatic FoxOs (L-FoxO1,3,4), we found that hepatic FoxOs were required for ApoM expression. Total plasma S1P levels were similar to those in controls, but S1P was nearly absent from HDL and was instead increased in the lipoprotein-depleted plasma fraction. This phenotype was restored to normal by rescuing ApoM in L-FoxO1,3,4 mice. Our findings show that insulin resistance in humans and mice is associated with decreased HDL-associated S1P. Our study shows that hepatic FoxO transcription factors are regulators of the ApoM/S1P pathway.