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J. Biol. Chem., Vol. 276, Issue 17, 14420-14425, April 27, 2001
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From the 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 125I-TTR revealed a ~90-kDa complex
corresponding to 125I-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 scavenger receptor SR-BI, a HDL
receptor, and known LDLr family hepatic receptors did not mediate TTR
uptake as assessed using different cellular systems. Interestingly, the
receptor-associated protein (RAP), a ligand for all members of the
LDLr, was able to inhibit TTR internalization. Moreover, the ~90-kDa
TTR-receptor complex obtained by cross-linking was sensitive to the
presence of RAP. To confirm that RAP sensitivity observed in hepatomas
did not represent a mechanism absent in normal cells, primary
hepatocytes were tested, and similar results were obtained. The
RAP-sensitive TTR internalization together with displacement of TTR
uptake by lipoproteins, further suggests that a common pathway might
exist between TTR and lipoprotein metabolism and that an as yet
unidentified RAP-sensitive receptor mediates TTR uptake.
Internalization of Transthyretin
EVIDENCE OF A NOVEL YET UNIDENTIFIED RECEPTOR-ASSOCIATED
PROTEIN (RAP)-SENSITIVE RECEPTOR*
§ and¶
Amyloid Unit, Instituto de Biologia
Molecular e Celular and the ¶ Instituto de Ciências
Biomédicas Abel Salazar, Universidade do Porto, 4150 Porto,
Portugal
*
This work was supported by Grant 2/2.1/BIA/459/94 from
PRAXIS XXI in Portugal. Part of this work was presented as an oral communication at the VIII International Symposium on Amyloidosis; de
Sousa, M., and Saraiva, M. J. Characterization of
Receptor-mediated Internalization of Transthyretin, Mayo Clinic,
August, 1998.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Amyloid Unit-IBMC,
R. Campo Alegre, 823 4150 Porto, Portugal. Tel.: 351-22-6074900; Fax:
351-22-6099157; mjsaraiv@ibmc.up.pt.
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