Studies of ApoD-/- and ApoD-/-ApoE-/- mice uncover the APOD significance for retinal metabolism, function, and status of chorioretinal blood vessels.

Apolipoprotein D (APOD) is an atypical apolipoprotein with unknown significance for retinal structure and function. Conversely, apolipoprotein E (APOE) is a typical apolipoprotein with established roles in retinal cholesterol transport. Herein, we immunolocalized APOD to the photoreceptor inner segments and conducted ophthalmic characterizations of ApoD-/- and ApoD-/-ApoE-/- mice. ApoD-/- mice had normal levels of retinal sterols but changes in the chorioretinal blood vessels and impaired retinal function. The whole-body glucose disposal was impaired in this genotype but the retinal glucose metabolism was unchanged. ApoD-/-ApoE-/- mice had altered sterol profile in the retina but apparently normal chorioretinal vasculature and function. The whole-body glucose disposal and retinal glucose utilization were enhanced in this genotype. OB-Rb, both leptin and APOD receptor, was found to be expressed in the photoreceptor inner segments and was at increased abundance in the ApoD-/- and ApoD-/-ApoE-/- retinas. Retinal levels of Glut4 and Cd36, the glucose transporter and scavenger receptor, respectively, were increased as well, thus linking APOD to retinal glucose and fatty acid metabolism and suggesting the APOD-OB-Rb-GLUT4/CD36 axis. In vivo isotopic labeling, transmission electron microscopy, and retinal proteomics provided additional insights into the mechanism underlying the retinal phenotypes of ApoD-/- and ApoD-/-ApoE-/- mice. Collectively, our data suggest that the APOD roles in the retina are context specific and could determine retinal glucose fluxes into different pathways. APOD and APOE do not play redundant, complementary or opposing roles in the retina, rather their interplay is more complex and reflects retinal responses elicited by lack of these apolipoproteins.

Emerging concepts of apolipoprotein D with possible implications for breast cancer.

Apolipoprotein D (ApoD) is a small glycoprotein of 24 kD, and a member of the lipocalin family. ApoD exerts several intracellular mechanistic roles, especially ligand binding. Some putative ligands are arachidonic acid, progesterone, and tamoxifen. It probably has a binding/reservoir function of these ligands in the cytoplasm. Furthermore, ApoD has features compatible with endosomal trafficking, proteolytic activity and interactions in cellular signal pathways. ApoD inhibits translocation of phosphorylated MAPK into the nucleus. Moreover, ApoD is associated with reduced proliferative activity of cancer cells, and is abundantly raised in senescent cells. In breast cancer, ApoD expression is associated with favourable histology and clinical stage, whereas in adjacent tumour stroma ApoD expression is a marker of adverse prognosis. Oestrogen receptor expression in breast cancer is inversely related to ApoD expression. Therefore, a combined oestrogen receptor positivity/ApoD positivity, could reflect a non-functional oestrogen receptor pathway, and this subset of breast cancer patients does not react to adjuvant tamoxifen treatment. The triangular relationship between oestrogen receptor, tamoxifen and ApoD should be further explored.

Identification of apolipoprotein D as a novel inhibitor of osteopontin-induced neoplastic transformation.

Osteopontin that associates with metabolism of calcium is one of the important factors in the development and prognosis of human breast cancer. The aim of this study was to detect potential binding partners of osteopontin to illustrate its functional mechanism. By screening a human breast cDNA library with a bacterial two-hybrid system, apolipoprotein D was isolated as a novel interacting protein of osteopontin. This interaction was confirmed by mammalian two-hybrid assay and co-immunoprecipitation. To elucidate the influence of ApoD on cellular neoplastic specifications, adhesion, soft agar, invasion and MTT growth assays were performed with Rama37 cells. The results revealed that expression of apolipoprotein D in Rama37 cells could significantly inhibit the malignant phenotype in osteopontin-transformed Rama37 cells. These findings provide better knowledge of the osteopontin signaling pathway and suggest that apolipoprotein D could be a prospective therapeutic agent for human breast and/or other carcinomas.