Hepatic FoxOs link insulin signaling with plasma lipoprotein metabolism through an apolipoprotein M/sphingosine-1-phosphate pathway.

Multiple beneficial cardiovascular effects of HDL are dependent 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 play a key role in mediating the effects of hepatic insulin action on glucose and lipoprotein metabolism. This work aims to determine whether hepatic insulin signaling regulates HDL-S1P, and the underlying molecular mechanisms.We report that insulin resistant, nondiabetic human subjects in two independent cohorts have decreased HDL-S1P levels, but no change in total plasma S1P. This also occurs in the mouse model of insulin resistance, db/db mice, which have low ApoM and a specific reduction of S1P in the HDL fraction, with no change in total plasma S1P. Using mice with hepatocyte deletion of the three insulin-repressible FoxO transcription factors (L-FoxO1,3,4), we found that hepatic FoxOs are required for ApoM expression and S1P association with HDL, without affecting total plasma S1P. In L-FoxO1,3,4 mice, total plasma S1P levels are similar to controls, but S1P is nearly absent from HDL, and is instead increased in the lipoprotein depleted plasma fraction. This phenotype is 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. Hepatic FoxO transcription factors are novel regulators of the ApoM-S1P pathway.