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Expression of human apolipoprotein E4 reduces insulin-receptor substrate 1 expression and Akt phosphorylation in the ageing liver.

Ong QR, Chan ES, Lim ML, Wong BS - FEBS Open Bio (2014)

Bottom Line: We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function.Liver cholesterol was not affected.These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

ABSTRACT
The diabetic drug rosiglitazone was reported to improve glucose tolerance in insulin-resistant ApoE3 but not ApoE4 knock-in mice. We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function. At 12 weeks, no difference in liver insulin signaling was detected between fasting ApoE3 and ApoE4 mice. At 72 weeks however, ApoE4 mice had lower IRS-1 and PI3K expression, and reduced Akt phosphorylation. This decline was associated with lower insulin and higher glucose in ApoE4 mouse liver. Liver cholesterol was not affected. These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

No MeSH data available.


Hepatic insulin receptor substrate and PI3K proteins expression in ApoE knock-in mice. (A) Western blot analysis of insulin receptor substrate-1 (IRS1), PI3K/p85 and PI3K/p110 levels in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of total (B) IRS1, (C) PI3K/p110 and (D) PI3K/p85 level relative to β-actin level in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower IRS1, PI3K/p85 and PI3K/p110 levels were detected in ApoE4 mice at 72 weeks of age as compared to ApoE3 mice of similar age. (∗p < 0.03; ∗∗p < 0.008, using Student’s t-test.)
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f0005: Hepatic insulin receptor substrate and PI3K proteins expression in ApoE knock-in mice. (A) Western blot analysis of insulin receptor substrate-1 (IRS1), PI3K/p85 and PI3K/p110 levels in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of total (B) IRS1, (C) PI3K/p110 and (D) PI3K/p85 level relative to β-actin level in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower IRS1, PI3K/p85 and PI3K/p110 levels were detected in ApoE4 mice at 72 weeks of age as compared to ApoE3 mice of similar age. (∗p < 0.03; ∗∗p < 0.008, using Student’s t-test.)

Mentions: At 12 weeks, insulin receptor substrate 1 (IRS1) expression does not differ between fasting ApoE3 and ApoE4 mice (Fig. 1A). At 72 weeks however, IRS1 expression is non-detectable in the fasting ApoE4 KI mice.


Expression of human apolipoprotein E4 reduces insulin-receptor substrate 1 expression and Akt phosphorylation in the ageing liver.

Ong QR, Chan ES, Lim ML, Wong BS - FEBS Open Bio (2014)

Hepatic insulin receptor substrate and PI3K proteins expression in ApoE knock-in mice. (A) Western blot analysis of insulin receptor substrate-1 (IRS1), PI3K/p85 and PI3K/p110 levels in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of total (B) IRS1, (C) PI3K/p110 and (D) PI3K/p85 level relative to β-actin level in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower IRS1, PI3K/p85 and PI3K/p110 levels were detected in ApoE4 mice at 72 weeks of age as compared to ApoE3 mice of similar age. (∗p < 0.03; ∗∗p < 0.008, using Student’s t-test.)
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f0005: Hepatic insulin receptor substrate and PI3K proteins expression in ApoE knock-in mice. (A) Western blot analysis of insulin receptor substrate-1 (IRS1), PI3K/p85 and PI3K/p110 levels in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of total (B) IRS1, (C) PI3K/p110 and (D) PI3K/p85 level relative to β-actin level in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower IRS1, PI3K/p85 and PI3K/p110 levels were detected in ApoE4 mice at 72 weeks of age as compared to ApoE3 mice of similar age. (∗p < 0.03; ∗∗p < 0.008, using Student’s t-test.)
Mentions: At 12 weeks, insulin receptor substrate 1 (IRS1) expression does not differ between fasting ApoE3 and ApoE4 mice (Fig. 1A). At 72 weeks however, IRS1 expression is non-detectable in the fasting ApoE4 KI mice.

Bottom Line: We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function.Liver cholesterol was not affected.These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

ABSTRACT
The diabetic drug rosiglitazone was reported to improve glucose tolerance in insulin-resistant ApoE3 but not ApoE4 knock-in mice. We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function. At 12 weeks, no difference in liver insulin signaling was detected between fasting ApoE3 and ApoE4 mice. At 72 weeks however, ApoE4 mice had lower IRS-1 and PI3K expression, and reduced Akt phosphorylation. This decline was associated with lower insulin and higher glucose in ApoE4 mouse liver. Liver cholesterol was not affected. These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

No MeSH data available.