Biology subjects

Izquierdo, M. C.

Publications and source records attributed to Izquierdo, M. C..

2 recordsLinked to original sources

bioRxiv2023

Insulin sensitization by hepatic FoxO deletion is insufficient to lower atherosclerosis in mice

BackgroundType 2 diabetes is associated with an increased risk of atherosclerotic cardiovascular disease. It has been suggested that insulin resistance underlies this link, possibly by altering the functions of cells in the artery wall. We aimed to test whether improving systemic insulin sensitivity reduces atherosclerosis. MethodsWe used mice that are established to have improved systemic insulin sensitivity: those lacking FoxO transcription factors in hepatocytes. Three hepatic FoxO isoforms (FoxO1, FoxO3, and FoxO4) function together to promote hepatic glucose output, and ablating them lowers glucose production, lowers circulating glucose and insulin, and improves systemic insulin sensitivity. We made these mice susceptible to atherosclerosis in two different ways, by injecting them with gain-of-function AAV8.mPcsk9D377Y and by crossing with Ldlr-/- mice. ResultsWe verified that hepatic FoxO ablation improves systemic insulin sensitivity in these atherosclerotic settings. We observed that FoxO deficiency caused no reductions in atherosclerosis, and in some cases increased atherosclerosis. These phenotypes coincided with large increases in circulating triglycerides in FoxO-ablated mice. ConclusionsThese findings suggest that systemic insulin sensitization is insufficient to reduce atherosclerosis. Non-standard Abbreviations and AcronymsLdlr, low-density lipoprotein receptor; TRL, triglyceride-rich lipoprotein; VLDL, very low-density lipoprotein

physiology↗

bioRxiv2019

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.

physiology↗