Increased low density lipoprotein receptor expression mediated through the insulin-like growth factor-I receptor in cultured fibroblasts.
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.
Ostlund
R E
RE
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Yang
J W
JW
Heath-Monnig
E
E
Semenkovich
C F
CF
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008969:Molecular Sequence Data; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000502:physiology*; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D011973:Receptors, LDL; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1