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

Abstract

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 insulinrepressible 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 the underlying molecular mechanisms. We report that insulin resistant, nondiabetic human subjects 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. 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 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. Hepatic FoxO transcription factors are regulators of the ApoM-S1P pathway.

The FoxOs are in the ApoM house

“…Of note, the authors targeted Foxo1,3,4 because of the compensation that can occur from each of these closely related F-box family members. Mechanistic experiments revealed that a constitutively active form of FoxO1 lacking the Akt phosphorylation sites increased Apom expression by 40% in primary murine hepatocytes, confirming that FoxO1 induces Apom in a cell-autonomous manner ( 5 ). FoxOs can also regulate gene transcription through indirect mechanisms ( 9 ).…”

“…The authors then performed ChIP-PCR assays to map FoxO1 occupancy at two promoter and two enhancer sites. Although they were unable to detect changes in FoxO1 signal between chow and high-fat diet treatments, they did detect binding events within all groups ( 5 ). We can interpret the absence of dynamic FoxO1 recruitment several ways with respect to transcription control: (a) gain and loss of FoxO1 may occur at de novo sites outside the chosen regions, as recently described in another study in which FoxO1 distribution at promoters and enhancers differed between genes involved in carbohydrate versus lipid metabolism ( 10 ); (b) FoxO1 could remain DNA bound, with the integrated transcriptional response governed by recruitment of corepressors or cooperativity between FoxO3,4, FoxA2, or other transcription factors known to colocalize with FoxOs, such as hepatocyte nuclear factor 4 (HNF4), CCAAT/enhancer binding protein β (CEBPβ), estrogen-related receptor α (ERRα), or the glucocorticoid receptor (GR) ( 11 , 12 ); (c) the high-fat diet may not have induced sufficient stress to alter FoxO1 activation as compared with other diabetic or insulin-resistant states.…”

“…In this issue of the JCI , Izquierdo et al explored the role of FoxO1,3,4 in the regulation of HDL-associated apolipoprotein M (ApoM) and sphingosine-1-phosphate (S1P) ( Figure 1 and ref. 5 ). Plasma ApoM mainly associates with HDL ( 6 ) and interacts with S1P ( 7 , 8 ).…”

“…These changes in insulin sensitivity associate with Akt and AMPK signaling via S1P receptor 1/3 activation ( 16 ). In contrast, Apom –/– mice, generated by inserting a neomycin resistance–encoding cassette in the ApoM locus, have increased glucose tolerance ( 18 ), while Izquierdo and colleagues demonstrated that rescuing the expression of ApoM in db/db mice failed to augment glucose tolerance ( 5 ). In addition, liver-specific knockdown of FoxO1,3,4 in mice decreased the HDL-ApoM-S1P complex, but also decreased hepatic glucose production ( 5 ).…”

“…Izquierdo and colleagues ( 5 ) demonstrated that hepatic FoxOs control plasma levels of HDL-ApoM-S1P1 in mice, providing insight into HDL function. HDLs protect against coronary artery disease (CAD) by promoting reverse cholesterol transport (RCT) and endothelial integrity and limiting inflammation and oxidation ( 20 ).…”