Foxo1 mediates insulin action on apoC-III and triglyceride metabolism

Abstract

The apolipoprotein apoC-III plays an important role in plasma triglyceride metabolism. It is predominantly produced in liver, and its hepatic expression is inhibited by insulin. To elucidate the inhibitory mechanism of insulin in apoC-III expression, we delivered forkhead box O1 (Foxo1) cDNA to hepatocytes by adenovirus-mediated gene transfer. Foxo1 stimulated hepatic apoC-III expression and correlated with the ability of Foxo1 to bind to its consensus site in the apoC-III promoter. Deletion or mutation of the Foxo1 binding site abolished insulin response and Foxo1-mediated stimulation. Likewise, Foxo1 also mediated insulin action on intestinal apoC-III expression in enterocytes. Furthermore, elevated Foxo1 production in liver augmented hepatic apoC-III expression, resulting in increased plasma triglyceride levels and impaired fat tolerance in mice. Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia. Moreover, we show that hepatic Foxo1 expression becomes deregulated as a result of insulin deficiency or insulin resistance, culminating in significantly elevated Foxo1 production, along with its skewed nuclear distribution, in livers of diabetic NOD or db/db mice. While loss of insulin response is associated with unrestrained apoC-III production and impaired triglyceride metabolism, these data suggest that Foxo1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia.

Docosahexaenoic acid suppresses the expression of FoxO and its target genes

“…For example, hepatic FoxO1 expression was elevated, along with increased nuclear localization, in the liver of diabetic NOD and db/db mice [36]. This elevation increases hepatic apoC-III expression, concomitant with increased plasma triacylglycerol levels and impaired glucose tolerance in mice [36].…”

FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes

“…Recent evidence indicates that FOXO1 may couple IR with low-grade inflammation. Augmented FOXO1 expression and activity were found in the liver of DIO or db/db mice characterized as models of IR and low-grade inflammation [19,23]. It has also been reported that FOXO1 increased expression of IL-1b in macrophages [24] and MCP-1 in adipocytes [25].…”

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

“…Interestingly, glucose induced APO-CIII transcription in hepatocytes through a mechanism involving the transcription factors ChREBP and HNF-4 [77]. Conversely, hepatic expression of APO-CIII was inhibited by insulin through insulin-dependent phosphorylation of FOXO1, resulting in its displacement from the nucleus and inability to drive APO-CIII transcriptional activity [78]. In hepatocytes, inhibition of APO-CIII transcription by fibrates was the consequence of multiple cooperative mechanisms including PPARa-driven displacement of HNF-4 from the APO-CIII promoter, inhibition of FOXO1 activation of APO-CIII transcription via the insulin-responsive element, and inhibition of glucosestimulated APO-CIII expression [76,79].…”