The Lipocalin Apolipoprotein D Functional Portrait: A Systematic Review

Abstract

Apolipoprotein D is a chordate gene early originated in the Lipocalin protein family. Among other features, regulation of its expression in a wide variety of disease conditions in humans, as apparently unrelated as neurodegeneration or breast cancer, have called for attention on this gene. Also, its presence in different tissues, from blood to brain, and different subcellular locations, from HDL lipoparticles to the interior of lysosomes or the surface of extracellular vesicles, poses an interesting challenge in deciphering its physiological function: Is ApoD a moonlighting protein, serving different roles in different cellular compartments, tissues, or organisms? Or does it have a unique biochemical mechanism of action that accounts for such apparently diverse roles in different physiological situations? To answer these questions, we have performed a systematic review of all primary publications where ApoD properties have been investigated in chordates. We conclude that ApoD ligand binding in the Lipocalin pocket, combined with an antioxidant activity performed at the rim of the pocket are properties sufficient to explain ApoD association with different lipid-based structures, where its physiological function is better described as lipid-management than by long-range lipid-transport. Controlling the redox state of these lipid structures in particular subcellular locations or extracellular structures, ApoD is able to modulate an enormous array of apparently diverse processes in the organism, both in health and disease. The new picture emerging from these data should help to put the physiological role of ApoD in new contexts and to inspire well-focused future research.

The Neuroprotective Lipocalin Apolipoprotein D Stably Interacts with Specific Subtypes of Detergent-Resistant Membrane Domains in a Basigin-Independent Manner

“…Such a mechanism would explain the known ability of ApoD in keeping lipid peroxidation levels under control (demonstrated in mammals at organism, tissue and cellular levels) [ 6 , 12 , 13 , 16 , 45 ], and preserved even when human ApoD function was tested in insect or plant model organisms [ 46 , 47 ]. Our findings are also coherent with the known antioxidant properties of ApoD-containing HDL 3 lipoparticles ([ 48 ], reviewed by [ 8 ]), and support the protective roles of ApoD within and outside the nervous system. ApoD-positive DRMs can be further fractionated by their different buoyancy, indicating the presence of ApoD in membrane subdomains with different physicochemical properties, and possibly present in different subcellular locations.…”

“…[ 6 , 7 ]). A recent systematic review on the apparently diverse functions carried out by ApoD within and outside the nervous system [ 8 ] supports a unique biochemical role: the management of cellular and extracellular lipid structures and their redox state. Two recent discoveries have triggered a complete change of paradigm, transforming our view of this finely regulated and evolutionary conserved lipid-binding protein.…”

“…Predictions for direct interaction of ApoD with cellular membranes can be formulated based on its association with lipoprotein particles [ 3 ] and liposomes [ 9 ], as well as on ApoD downstream effects on lipid peroxidation studied at organismal, cellular and molecular levels [ 9 , 13 , 16 ]. This property is evidenced by ApoD immunoreactivity at the plasma or intracellular organelle membranes, first observed by Boyles et al [ 17 ] and recently demonstrated by immunogold electron microscopy ([ 12 , 18 ], reviewed by [ 8 ]). Nevertheless, in spite of all the advancements in the understanding of ApoD biology and functional consequences for brain health and disease, we still need to elucidate how ApoD interacts with relevant cellular membranes if we want to understand its mechanism of action at the molecular level.…”

“…Candidate ApoD receptors have been postulated from experiments where downstream consequences of ApoD exposure are modified by antagonists of some receptors (LDLR, CXCR-4) [ 19 ], or by biochemical approaches combining classic two-hybrid systems with co-immunoprecipitation experiments. The later approach has reported two transmembrane glycoproteins (CD147/Basigin (BSG) [ 20 ] and the Scavenger receptor class B type 1 (SRB1) [ 21 ]) and an extracellular glycoprotein, osteopontin (OPN) [ 22 ], as candidate ApoD protein interactors (reviewed by [ 8 ]). However, two independent evidences indicate that ApoD is able to interact with lipidic structures without requiring a protein–protein contact: (i) the direct antioxidant action of ApoD on phospholipid vesicles [ 9 ], and (ii) that ApoD-LDL interaction is hampered in the presence of detergent, and requires the presence of the hydrophobic surfaces on the protein [ 23 ].…”

The known unknowns of apolipoprotein glycosylation in health and disease

“…The absence of N- glycans on ApoD negatively affects the activity of LPL ( Perdomo et al., 2010 ). ApoD levels positively correlates with signaling cascades associated with stress, inflammation, cancer, cardiovascular, and neurodegenerative conditions ( Sanchez and Ganfornina, 2021 ). Sialylated ApoD glycoforms correlate with autism spectrum disorder (ASD).…”