LCAT-null mice develop improved hepatic insulin sensitivity through altered regulation of transcription factors and suppressors of cytokine signaling

Abstract

We previously reported that LCAT-deficient mice develop not only low HDL-cholesterol but also hypertriglyceridemia, hepatic triglyceride (TG) overproduction, and, unexpectedly, improved hepatic insulin sensitivity and reduced hepatic TG content. Here, we examined the mechanistic links underlying this apparent paradox. The LDL receptor-deficient (Ldlr)(-/-)xLcat(-/-) mouse model and age- and sex-matched Ldlr(-/-)xLcat(+/+) littermates, both in C57Bl/6 background, were employed. Studies of hepatic insulin signal transduction showed an upregulation of hepatic Irs2 mRNA level (5.3-fold, P = 0.02), IRS-2 protein mass level (1.5-fold, P = 0.009) and pIRS-2 (1.8-fold. P = 0.02) in the Ldlr(-/-)xLcat(-/-) mice. There was a 1.2-fold increase in pAkt (P = 0.03) with a nonsignificant change in total Akt. We observed a significant shift in its downstream transcription factor FoxO-1 to the cytosolic compartment (2.3-fold increase in cytosolic/nuclear ratio, P = 0.04). We also observed a significant 3.1-fold increase in nuclear abundance of FoxA-2 mass (P = 0.017) and a 1.5-fold upregulation of its coactivator PGC-1beta (P = 0.002), the coordinated actions of which promotes hepatic TG production and beta-oxidation. Increased hepatic insulin signaling in the Ldlr(-/-)xLcat(-/-) mice was associated with an upregulation of the Tcfe3 gene (1.7-fold, P = 0.024), a selective downregulation of the Socs-1 gene by 60% (P = 0.01), and no change in PTP-1B protein mass. These data suggest that LCAT deficiency induces complex alterations in hepatic signal transduction cascades, which explain, at least in part, the observed enhanced insulin signaling in association with hepatic TG overproduction and reduced hepatic TG content.