Increased low density lipoprotein receptor expression mediated through the insulin-like growth factor-I receptor in...

Plasma insulin-like growth factor-I (IGF-I) levels are inversely correlated with apolipoprotein B and low density lipoprotein (LDL) cholesterol in humans. To identify a molecular basis for this observation, the effects of IGF-I on LDL receptor expression in fibroblasts were studied. IGF-I increased LDL receptors in cultured human skin fibroblasts at concentrations greater than 25 ng/ml. However, IGF-I effects were not easily quantitated due to secretion of inhibitory IGF-binding proteins by the cells. To circumvent this difficulty, QAYL, an IGF-I analog that binds to the IGF-I receptor but not to IGF-binding proteins, was used. QAYL increased LDL receptor number 56-72% with half-maximum effect at 0.6 ng/ml. alpha-IR3, a monoclonal antibody directed toward the IGF-I receptor, blocked this effect. QAYL treatment increased synthesis of LDL receptor protein without increasing LDL receptor mRNA levels or altering protein stability. Both QAYL and IGF-I increased LDL receptors prominently in cells that had been treated with physiological amounts of LDL cholesterol. IGF-I, acting through the IGF-I receptor and modulated by IGF-binding proteins, may contribute to the regulation of LDL metabolism by increasing translation of LDL receptor message.