Abstract
Patients with diabetes suffer disproportionately from impaired lipid metabolism and cardiovascular disease, but the relevant roles of insulin resistance and hyperglycemia in these processes are unclear. Transcription factor FoxO1 is regulated dually by insulin and nutrients. In this study, we addressed the hypothesis that, in addition to its established role to regulate hepatic glucose production, FoxO1 controls aspects of lipid metabolism in the diabetic liver. Mice with a liver-specific deletion of FoxO1 (L-FoxO1) and their control littermates were rendered hyperglycemic by streptozotocin administration. Subsequently, we monitored serum lipids, liver VLDL secretion, and hepatic expression of genes related to lipid metabolism. Hepatic FoxO1 ablation resulted in increased VLDL secretion, increased cholesterol, and increased plasma free fatty acids, three hallmarks of the diabetic state. l-FoxO1 mice expressed increased levels of SREBP-2 and FGF21 without affecting lipogenic genes. We propose that FoxO1 fine tunes lipolysis through its actions on FGF21 and that hepatic FoxO1 ablation increases availability of substrates for hepatic triglyceride and cholesterol synthesis and VLDL secretion. The implications of these findings are that FoxO1 protects against excessive hepatic lipid production during hyperglycemia and that its inhibition by intensive insulin treatment may exacerbate paradoxically the lipid abnormalities of diabetes.
Highlights
Nonexclusive causes have been proposed: insulin resistance and hyperglycemia
These results indicate that hepatic FoxO1 ablation causes inappropriately high expression of FGF21, an inducer of adipose TG lipolysis, during hyperglycemia
Despite the rise in PPAR␣ and its target genes, ketone levels are similar in liver-specific FoxO1 knock-out mice (L-FoxO1) and control mice, suggesting that the liver is unable to oxidize the excessive supply of FFAs, which are instead channeled into esterification, resulting in elevated VLDL secretion
Summary
Mice—L-FoxO1 mice were described previously [10] and were fed a standard chow diet. Male mice, with an average age of 14 –20 weeks, were injected intraperitoneally with streptozotocin (Sigma-Aldrich) at a dose of 225 mg/kg or a similar volume of 0.9% saline. Measurements from untreated and salinetreated mice were combined, as there were no differences due to saline. Liver lipid content (n ϭ 5–7) was measured by Folch extraction [17] and confirmed by both Oil Red O staining of snap-frozen liver sections and saponification in ethanolic KOH as described previously [18]. Serum Lipoprotein Analysis and TG Production—For FPLC analysis, sera from three mice per genotype were pooled after a 5-h fast and separated as described [19]. TG production was measured by intravenous injection of Triton WR 1339 (Tyloxapol, Sigma) at 500 mg/kg followed by serum collection at 1 and 2 h post-injection. Post-Triton serum samples were separated by density ultracentrifugation as described [19]. Data were analyzed by either two-way analysis of variance followed by post hoc Tukey tests, or two-tailed Student’s t tests, where appropriate
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