Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

The FoxO family of transcription factors play an important role in mediating insulin action on glucose, lipid, and lipoprotein metabolism. Liver-specific triple FoxO knockout mice (L-FoxO1,3,4) have defects in expression of genes related to glucose production, bile acid synthesis, and high density lipoprotein (HDL)-cholesterol uptake. We have now identified Apolipoprotein M (Apom) as a novel transcriptional target of liver FoxO. ApoM is a liver-secreted apolipoprotein that is bound to HDL in the circulation, and it serves as a chaperone for the bioactive lipid, sphingosine-1-phosphate (S1P). Several recent studies have demonstrated that S1P bound to ApoM induces unique effects, compared to S1P bound to albumin. We now show that liver FoxOs are required for ApoM mRNA and protein expression, and that ApoM is a transcriptional target of FoxOs. Moreover, while total plasma S1P levels are similar between control and L-FoxO1,3,4 mice, S1P is nearly absent from HDL in L-FoxO1,3,4 mice, and is instead increased in the lipoprotein depleted fraction. We also observed that leptin receptor deficient db/db mice have low hepatic Apom mRNA, and low levels of ApoM and S1P in HDL, without changes in total plasma S1P. These data demonstrate that FoxO transcription factors are novel regulators of the ApoM-S1P pathway, and indicate a potential link between hepatic insulin action and HDL function.