Novel Mechanisms for Posttranscriptional Regulation of LDL Receptors

  • Post, Steven (PI)

Grants and Contracts Details


Defects in low density lipoprotein (LDL) internalization are associated with increased risk of atherosclerosis and heart disease. The best characterized of these defects are mutations in the LDL receptor (LDLR) that result in decreased receptor internalization. In addition, recent evidence suggests that a mutation in the autosomal-recessive hypercholesterolemia (ARH) protein, a putative adaptor protein expressed in the liver, results in hypercholesterolemia. Although a specific role for ARH in regulating LDL metabolism has yet to be defined, the severe hypercholesterolemia that occurs in individuals with mutations in this gene indicates a crucial role for ARH in regulating LDLR function. Taken further, the association between genetic defects in an adaptor protein and decreased LDL uptake indicates that the interaction between LDLR and cytosolic adaptor proteins is an important, previously unrecognized posttranscriptional mechanism for regulating LDLR endocytosis. In addition to a hepatocyte-specific interaction with ARH, LDLR associate with cytosolic proteins of the disabled family (i.e., Dab1 and Dab2). Dab2 is expressed in a variety of cell types including macrophages. Moreover, Dab2 colocalizes with both LDLR and the endocytic protein alpha-adaptin in clathrin-coated pits suggesting that Dab2 is an adaptor for LDLR. Thus, Dab2 might regulate LDLR uptake in non-hepatic cells in a manner analogous to ARH in hepatocytes. Indeed, our data suggest that LDLR-dependent lipoprotein uptake in macrophages is regulated by a specific interaction of LDLR with an adaptor protein (e.g., Dab2). Specifically, we found that LDLR-dependent lipoprotein uptake was enhanced by acute treatment with Macrophage Colony-Stimulating Factor (M-CSF) via a Gi/o-dependent signaling pathway. Increased LDLR-mediated lipoprotein uptake was not associated with increased receptor expression or increased transferrin receptor (TfR) internalization suggesting that the LDLR contains cytoplasmic sequences that permit specific regulation by intracellular signaling pathways. Furthermore, M-CSF treatment increased the colocalization of LDLR and Dab2. Thus, Dab2 may act as an endocytic adaptor protein for LDLR and regulate the effects of M-CSF on LDLR endocytosis.The current proposal will test the hypothesis that activation of intracellular signaling pathways modulates LDLR-mediated endocytosis by regulating the interaction between the LDLR and the specific intracellular adaptor protein, Dab2.
Effective start/end date1/1/0312/31/03


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