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

•Emerging studies suggest that ApoE has other functions beyond cholesterol metabolism.•At 32-weeks, insulin signaling was similar in both ApoE3 and ApoE4 knock-in mice.•At 72-weeks, IRS1 and PI3K expression and Akt phosphorylation were reduced in ApoE4 mice.•Aged huApoE4 mice also have lower liver insulin but higher glucose content.•This shows an ApoE genotype-dependent effect on liver insulin signaling during ageing.

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.