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.

The FoxO transcription factors and metabolic regulation

“…In diabetic NOD and Lepr db/db mice, hepatic FoxO1 expression was deregulated, as evidenced by elevated FoxO1 production along with its increased nuclear localization in liver. These data suggested that FoxO1 deregulation associated with insulin deficiency or insulin resistance played an important role in linking impaired insulin action to aberrant apoC-III production in the pathophysiology of diabetic hypertriglyceridemia [77]. In contrast, acute overexpression of a constitutively nuclear FoxO1 affects hepatic glucose and lipid metabolism alternatively.…”

ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice

“…Aliquots of blood (25 l) were taken from the tail vein at different times for determining plasma TG, as described (36).…”

“…Cells were cultured in Dulbecco's modified Eagle's medium (DMEM, Lonza, Walkersville, MD) and were transduced with Adv-ATF4 or control Adv-Empty vector as described (38). All adenoviral vectors were produced in HEK293 cells, as described (36).…”

The expression of type III hyperlipoproteinemia: involvement of lipolysis genes

“…The presence of the APOC3 -455 and -482 polymorphisms may abolish the insulin responsiveness of the APOC3 promoter. 48,49 As the APOC3 3238 G4C polymorphism in E2/2 subjects is almost exclusively found in combination with the presence of the -455 and -482 promoter variants, it seems possible that in E2/2 subjects, who are carriers of the 3238 G4C polymorphism, the loss of insulin regulation results in overexpression of the APOC3 gene and, as a consequence, in overt hyperlipidemia. 12,34 In addition, insulin is a major regulator of LPL activity.…”