Brief Reports

Assignment of the Human Tear Lipocalin Gene (LCN1) to 9q34 by in Situ Hybridization

The lipocalin (LCN) family members, a group of small extracellular proteins with 160-180 amino acids in length, can be detected in all kingdoms of life from bacteria to human beings. They are characterized by low similarity of amino acid sequence but highly conserved tertiary structures with an eight-stranded antiparallel β-barrel which forms a cup-shaped ligand binding pocket. In addition to bind small hydrophobic ligands (i.e., fatty acids, odorants, retinoids, and steroids) and transport them to specific cells, lipocalins (LCNs) can interact with specific cell membrane receptors to activate their downstream signaling pathways, and with soluble macromolecules to form the complex. Consequently, LCNs exhibit great functional diversity. Accumulating evidence has demonstrated that LCN family proteins exert multiple layers of function in the regulation of many physiological processes and human diseases (i.e., cancers, immune disorders, metabolic disease, neurological/psychiatric disorders, and cardiovascular disease). In this review, we firstly introduce the structural and sequence properties of LCNs. Next, six LCNs including apolipoprotein D (ApoD), ApoM, lipocalin 2 (LCN2), LCN10, retinol-binding protein 4 (RBP4), and Lipocalin-type prostaglandin D synthase (L-PGDS) which have been characterized so far are highlighted for their diagnostic/prognostic values and their potential effects on coronary artery disease and myocardial infarction injury. The roles of these 6 LCNs in cardiac hypertrophy, heart failure, diabetes-induced cardiac disorder, and septic cardiomyopathy are also summarized. Finally, their therapeutic potential for cardiovascular disease is discussed in each section.

The lipocalins make up a heterogeneous superfamily of proteins. Although showing almost no sequence homology, they share very similar secondary and tertiary structures. Their ability to bind hydrophobic ligands is well established, but the physiological function of most lipocalins remains unclear. The lipocalin from the human Von Ebner's Gland of the tongue (VEGh) contains three sequence motifs corresponding with the papain-binding domains of cystatins, a family of naturally occurring cysteine proteinase inhibitors. We found that VEGh inhibited papain activity to a similar extent as salivary cystatin S. Furthermore, synthetic peptides derived from VEGh and cystatin C, comprising these three motifs, inhibited papain, too. We conclude that VEGh is a physiological inhibitor of cysteine proteinases and therefore can play a role in the control of inflammatory processes in oral and ocular tissues.

The lipocalin superfamily encompasses a large set of quite distantly related proteins that act as carriers for small, lipophilic molecules. The lipocalin genes coding for orosomucoid, the α₁-microglobulin/bikunin precursor, and the major urinary protein map to MMU4, while their human counterparts map to the homologous HSA9q34 area where three other lipocalin genes for complement C8 γ chain (C8G), progestagen-associated endometrial protein (PAEP), and prostaglandin D synthase (PTGDS) are also located. By linkage analyses in an interspecific backcross progeny in mouse, the Lcn2 gene coding for the oncogenic lipocalin 24p3, as well as the 3 lipocalin genes for C8G, PTGDS, and PAEP, have now been assigned to MMU2. The first three genes map to proximal MMU2, which is known to be homologous to HSA9q34. Paep is more distally located, which extends the number of regions with conserved syntenies between HSA9q34 and MMU2. By in situ hybridization, the human LCN2 gene maps to HSA9q34. Our data indicate that the lipocalin locus arrangement in the human/mouse ancestor is closer to that found at HSA9q than to that in the MMU genome.