Insulin‐like growth factor I (IGF‐1) downregulates lipoprotein lipase and suppresses atherosclerotic foam cell formation in vivo and in vitro

Abstract

We have shown that IGF‐1 decreases atherosclerosis in ApoE‐null mice. Lipoprotein lipase (LPL) increases the uptake of OxLDL by macrophages (MΦ), promoting foam cell formation and atherosclerosis development. To determine a potential effect of IGF‐1 on LPL and foam cell formation, we infused ApoE‐null mice with 1.5 mg/kg IGF‐1 or saline for 12w. IGF‐1 reduced aortic LPL mRNA levels by 31% (RT‐PCR) and serum LPL activity by 66% (fluorescence assay). This effect correlated with a 27% reduction in Oil Red‐positive lesion area and a 36% decrease in plaque MΦ (immunostaining with Mac‐3 a/b) suggesting that IGF‐1 reduced MΦ‐derived foam cell formation.Human blood monocyte‐derived MΦ were treated with 80 ug/ml OxLDL for 48h to stimulate formation of Oil Red‐positive "foam cells". OxLDL increased MΦ LPL mRNA levels and LPL activity >5‐fold. Pre‐treatment with IGF‐1 (25 ng/ml, 24h) reversed OxLDL‐induced upregulation of LPL activity by 52% and decreased lipid uptake by 88%. Furthermore, adenovirus‐mediated overexpression of IGF1 receptor in MΦ prevented lipid uptake by 82% vs. control Ad‐GFP‐infected MΦ. Conversely, addition of exogenous LPL (5 ug/ml) stimulated DiI‐OxLDL binding by MΦ by 2.3‐fold and increased lipid uptake by 1.9‐fold (Oil Red‐staining). Liver X receptor (LXR) is a nuclear transcription factor regulating MΦ LPL expression. The LXR agonist 22R‐oxycholesterol (50 uM, 16h) increased LPL activity in MΦ >2‐fold and IGF‐1 reversed this effect by 65%. In summary, our data indicate that IGF‐1 downregulates LPL in vivo and in vitro potentially via a LXR‐dependent mechanism and inhibits foam cell formation. This is the first report of an effect of IGF‐1 on cellular lipid internalization and these findings have major relevance for the understanding of mechanisms whereby IGF‐1 reduces atherosclerosis.