Apolipoprotein D

Apolipoprotein D (apoD) is a 29-kDa 169-amino acid glycoprotein that is primarily associated with high density lipoproteins in human plasma. A fraction of human apoD, like other cysteine-containing apolipoproteins, exists as a disulfide-linked heterodimer with other apolipoproteins and lecithin/choles­terol acyltransferase. It is an atypical apolipoprotein and, based on its primary structure, apoD is predicted to be a member of the lipocalin family. It has a high degree of homology to plasma retinol-binding protein. Similarity of intron locations in both apo D and RBP suggests that these two genes derived from a common ancestor. Lipocalins adopt a beta-barrel tertiary structure and transport small hydrophobic ligands. Although apoD can bind cholesterol, progesterone, pregnenolone, bilirubin and arachidonic acid, it is unclear if any, or all of these, represent its physiological ligands.

It has been also identified as the carrier of the most abundant male odor component E-3-methyl-2-hexenoic acid (E-3M2H).

It was also proposed that the affinity of HDL for bilirubin is primarily the result of binding to apo D. While its role in metabolism has yet to be defined, apoD is likely to be a multi-ligand, multi-functional transporter. It could transport a ligand from one cell to another within an organ, scavenge a ligand within an organ for transport to the blood or could transport a ligand from the circulation to specific cells within a tissue.

Apolipoprotein D mRNA has been detected in human liver, intestine, pancreas, kidney, placenta, adrenal, spleen, and fetal brain tissue. Progesteronebinding protein GCDFP-24, the major protein found in human breast gross cystic disease fluid, corresponds to apolipoprotein-D.. Apolipoprotein D has been also found in human tear fluid. Unlike serum, it seems that in the tear fluid apoD exists mainly as a disulphide linked homodimer which is not associated with lecithin/choles­terol acyltransferase (LCAT) or apolipoprotein A-I (apo A-I).

Apolipoprotein D regulation

IL-6 is a potent inhibitor of basal as well as androgen-, glucocorticoid- and IL-1 alpha-induced apo-D secretion in ZR-75–1 human breast cancer cells. Apolipoprotein D is strongly up-regulated by retinoic acid (RA) in breast cancer cells. 1,25-dihydroxyvitamin D3 strongly up-regulated apoD mRNA levels in T-47D human breast cancer cells in a time- and dose-dependent manner.

Fibroblasts, the common cell-type expressing apoD mRNA in vivo, express this characteristic following growth-arrest.

Apolipoprotein D action

ApoD plays an important role in the homeostasis or housekeeping of probably all organs. One of its functions is likely to be the transport of a hydrophobic ligand (a lipid) in a one-to-one molar ratio with itself. This transport is likely to occur unidirectionally between neighboring cells in an organ, and between perivascular cells and the blood circulation. The chemical structure of the natural ligand, or ligands, of ApoD in normal cells in vivo or in culture is not known, but ApoD has been shown to bind some steroids and bilirubin.

Apolipoprotein D and Neural Tissue

ApoD may be an acute phase neural protein that is upregulated in a variety of neuropathological conditions and is involved in the removal of lipids during nerve cell degeneration and provision of lipids during the regenerative phase.

In regenerating crushed nerve, the steady-state level of ApoD mRNA transiently increased at least 40-fold above control levels at the time when axons from the proximal stump grow into the distal nerve segment. High level expression of ApoD mRNA seems to be a novel regeneration-associated molecular event of endoneurial fibroblasts indicating a function for ApoD and fibroblasts in nerve repair.

Impact brain trauma caused induction of ApoD expression in the cortex and hippocampus in the rat.

ApoD is constitutively secreted by astrocytes with little intracellular storage. The secreted apoD floated primarily at density 1.063–1.21 g ml-1 upon sequential ultracentrifugation indicating its association with lipids.

ApoD immunoreactivity was found in neuroglial cells of white matter in all sampled brain regions studied but also in pial cells and perivascular cells. Immunoreactive neurons do not present a uniform pattern throughout the gray matter. The pons and the brainstem show a high immunoreactivity for ApoD in several nuclei (olivary, arciforme, cuneado, raphe). In the cerebellum the immunoreactivity appears in some neurons of the Purkinje layer. Finally in the cerebral cortex ApoD positive neurons were not observed. These results suggest that ApoD role may vary depending of a cellular synthesis or location.

Increased ApoD levels were found in the hippocampus and in CSF of Alzheimer disease patients and proposed to be a marker of neuropathology, including that associated with AD. It was proposed that, although increases in ApoD expression are a normal feature of brain aging, super-increases may represent a glial cell compensatory response to beta-amyloid deposition in Alzheimer‘s di­sease.

Chronic administration of the atypical antipsychotic drug, clozapine, to rodents has been shown to increase the concentration of apolipoprotein D (apoD) in several areas of the brain, suggesting that ApoD could be involved in the therapeutic effects of antipsychotic drugs and/or the pathology of psychotic illnesses. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027–0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.

Plasma apoD levels were elevated in never-medicated patients at the firstepisode of psychosis compared to normals (P = 0.047).

Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders.

It was found that long-term clinical outcome of schizophrenia was associated with the ApoD polymorphism rs7659 (P = 0.041) following adjustment for lifetime clinical global impression, age at first admission and gender.

Exogenous apoD added directly to the incubation media prevented cellular uptake of free [3H]arachidonic acid. These results suggest that apoD acts to stabilize membrane-associated arachidonic acid by preventing release and sequestering free arachidonic acid in the cell. These actions of apoD may be beneficial to psychiatric patients.

Multiple sclerosis (MS) is characterized by an increased intrathecal apoD release. Moreover, it was demonstrated that mean apoD indices are highest in MS patients at the time of their first clinical exacerbation. CSF apoD levels and apoD indices correlate with MS disease duration but not with disability or age. Finally, it was found that corticosteroid treatment resulted in significantly elevated CSF apoD levels.

Apolipoprotein D and Cancer

Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells.

Apolipoprotein D in Urine

Apolipoprotein D has been identified in normal human urine, Apolipoprotein D behaves uniquely as regards its excretion in urine; the other apolipoproteins belonging to the A, B, D and E groups, although of low molecular masses, are present, at most, in trace amounts in normal urine. ApoD in urine exists as a mixture of monomers and dimers, the latter having apparent molecular weights different from those occurring in plasma. Although not as sensitive an indicator for tubular proteinuria as alpha 1-microglobulin, apolipoprotein D, being a storage-stable urinary protein, seems a valuable complement for the diagnosis of tubular malfunction.

Catalog Number	Protein	Source	Size
RD172118100	Apolipoprotein D (ApoD, Apo-D) Human (E.coli)	E. coli	0.1 mg
RD172118100+	Apolipoprotein D (ApoD, Apo-D) Human (E.coli)	E. coli	10 x 0.1 mg