Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia - PubMed (original) (raw)

Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia

Rebecca A Haeusler et al. J Biol Chem. 2010.

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.

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Figures

FIGURE 1.

FIGURE 1.

Metabolic characteristics of fasting and refeeding in untreated and STZ-treated mice. A–C, serum TG, cholesterol, and NEFA in untreated or STZ-treated mice, fasted overnight (n = 16–44) or fasted overnight then refed for 4 h (n = 5–10). D, blood glucose levels 1 week after STZ injection (n = 5–57 per group). E–F, hepatic TG and cholesterol in untreated or STZ-treated mice, fasted overnight or fasted overnight then refed for 4 h (n = 5–7). For blood glucose, *, p < 0.05 by two-tailed Student's t test. For all other analyses, *, p < 0.05 and **, p < 0.01 by two-way analysis of variance.

FIGURE 2.

FIGURE 2.

Serum lipoprotein analysis. A–B, shown are TG and cholesterol in FPLC-separated lipoprotein fractions from 5-h fasted STZ-treated control and

l

-FoxO1 mice. Sera were pooled from three mice per genotype. C, shown is the serum TG accumulation after Triton WR 1339 injection (n = 6–9 per group). Shown are TG (D) and cholesterol (E) from the VLDL fraction 2 h after Triton injection. F, VLDL and LDL ApoB proteins were analyzed by SDS-PAGE followed by Coomassie blue staining (n = 6 per group). G, shown is the quantitation of ApoB48 and ApoB100 (n = 6 per group). *, p < 0.05 and **, p < 0.01 by two-tailed Student's t test.

FIGURE 3.

FIGURE 3.

LDL receptor protein visualized by Western blot in STZ-treated control and l-FoxO1 mice that were fasted overnight and subsequently refed for 4 h.

FIGURE 4.

FIGURE 4.

FGF21 expression. A, FGF21 mRNA from livers of untreated or STZ-treated mice, fasted overnight or fasted overnight then refed for 4 h (n = 5–9 per group). For comparison, quantitative PCR analyses were combined from three separate 96-well plates: untreated fasted versus untreated refed; untreated fasted versus STZ-treated fasted; and STZ-treated fasted versus STZ-treated refed. Each sample was measured in triplicate. B, serum FGF21 levels after a 24 h fast in untreated or STZ treated mice (n = 6–12). C, serum β-hydroxybutyrate (n = 9–13). D, the ratio of serum FGF21 to β-hydroxybutyrate was calculated for individual mice; the mean of these ratios is presented (n = 6–12). E, ratio of serum FGF21 to β-hydroxybutyrate in STZ-treated mice, separated by strain background. Mixed background line is ∼80% B6 and 15% 129, with minor contributions from FVB and DBA. The B6 line is ∼97% B6. Ratios were calculated for individual mice; the mean of these ratios is presented (n = 4–7). *, p < 0.05 and **, p < 0.01 by two-way analysis of variance.

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