Transthyretin (TTR) is a plasma carrier of thyroxine and retinol-binding protein (RBP). Though the liver is the major site of TTR degradation, its cellular uptake is poorly understood. We explored TTR uptake using hepatomas and primary hepatocytes and showed internalization by a specific receptor. RBP complexed with TTR led to a 70% decrease of TTR internalization, whereas TTR bound to thyroxine led to a 20% increase. Different TTR mutants showed differences in uptake, suggesting receptor recognition dependent on the structure of TTR. Cross-linking studies using hepatomas and (125)I-TTR revealed a approximately 90-kDa complex corresponding to (125)I-TTR bound to its receptor. Given previous evidence that a fraction of TTR is associated with high-density lipoproteins (HDL) and that in the kidney, megalin, a member of the low-density lipoprotein receptor family (LDLr) internalizes TTR, we hypothesized that TTR and lipoproteins could share related degradation pathways. Using lipid-deficient serum in uptake assays, no significant changes were observed showing that TTR uptake is not lipoprotein-dependent or due to TTR-lipoprotein complexes. However, competition studies showed that lipoproteins inhibit TTR internalization. The scaven...Continue Reading
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Scavenger Receptor Class B Member 1 Independent Uptake of Transthyretin by Cultured Hepatocytes Is Regulated by High Density Lipoprotein
Naso-maxillary deformity due to frontonasal expression of human transthyretin gene in transgenic mice
Retinoids modulate expression of the endocytic partners megalin, cubilin, and disabled-2 and uptake of vitamin D-binding protein in human mammary cells
Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell
Genetic and environmental contributions to serum retinol and alpha-tocopherol concentrations: the Stanislas Family Study
Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies
Plasma Proteome Profiling of Coronary Artery Disease Patients: Downregulation of Transthyretin-An Important Event
Binding of amyloidogenic transthyretin to the plasma membrane alters membrane fluidity and induces neurotoxicity
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