Lactosylceramide plays a vital role in the biosynthesis of many glycosphingolipids, and therefore, the biochemical mechanisms involved in its regulation can have a major impact on its bioactivity and that of related compounds. This review focuses on the role of low density lipoprotein (LDL)-mediated regulation of lactosylceramide biosynthesis. We present evidence indictating that in normal cells having functional LDL receptors there is an LDL-mediated suppression of lactosylceramide biosynthesis via regulating UDP-Gal: glucosylceramide 1, 4 galactosyltransferase (GalT-2). In contrast, when there is a lack of LDL receptors, as for example in patients with homozygous familial hypercholesterolemia or kidney cancer, LDL enters the cell via a LDL receptor-independent pathway (“scavenger pathway”), up-regulates GalT-2 and increases the cellular levels of lactosylceramide. This review also discusses the role of GalT-2, action in signal transduction of oxidized LDL leading to cell proliferation in aortic smooth uscle cells, a hallmark in the pathophysiology in atherosclerosis. A.
The participation of complex gangliosides in the adhesion process was suggested initially by the knowledge that these cell surface components can recognize several bioactive factors in the extracellular environment, including fibronectin. Therefore, early studies tested the possibility that complex gangliosides functioned as receptors for fibronectin. However, a receptional role of gangliosides for fibronectin was never demonstrated convincingly. Moreover, the identification of integrins cell surface glycoprotein receptors for matrix adhesive proteins-cast in doubt any role for gangliosides in cell adhesion. Subsequently, it was observed that the molecular assembly of adhesion sites-i. e. those structures which mediate the adhesion of cells to tissue culture substrata-implied the preferential distribution of complex gangliosides. Moreover, complex gangliosides were found to colocalize with integrin receptors in adhesion sites. These observations renewed interest in the involvment of complex gangliosides in cell adhesion, pointing to an interaction of complex gangliosides with other components of adhesion sites, such as integrins. Indeed, gangliosides were shown to affect integrin function by modulating the affinity of integrin receptors for their ligands in the extracellular matrix (fibronectin and vitronectin). Furthermore, the modulation of integrin function by gangliosides was demonstrated to influence the differentiation of neuronal cells. Thus, complex gangliosides may represent membrane-associated regulators of integrin functions.
A series of relatively small glycoproteins, normally localized in the lysosome, function as co-factors for physiological degradation of sphingoglycolipids with short hydrophilic head groups. Genetic deficiencies of the GM2 activator protein result in a clinical and biochemical phenotype essentially indistinguishable from the classical infantile form of Tay-Sachs disease. A single gene localized on human chromosome 5 codes for the GM2 activator protein. Genetic deficiencies of two homologous proteins, sap-B and sap-C, cause disorders resembling metachromatic leukodystrophy and Gaucher disease, respectively. Additional two putative activator proteins, sap-A and sap-D, are also known to activate degradation of some sphingolipids in vitro. However, the physiological significance of sap-A and sap-D in vivo has not been established. No disease state is known caused by specific genetic defects in either sap-A or sap-D. The four sap proteins are all homologous to each other and are generated by a single precursor translation product of the gene on chromosome 10, presumably by post-translational proteolytic processing. Recently, two patients have been identified in a single family in whom a mutation had occurred in the initiation codon of the sphingolipid activator gene. The patients' fibroblasts are totally deficient with the precursor protein and consequently with all four sphingolipid activator proteins. The patients showed a complex pathology and abnormal storage of several sphingolipids, suggesting that sap-A and sap-D also have in vivo activator functions but not necessarily on those lipids reported to be the substrates in in vitro experiments. For example, despite the in vitro activation of sphingomyelin degradation by three of the sap proteins (B, C, D), there was no abnormality in tissue sphingomyelin levels in these patients. These genetic disorders help clarifying the specificities of the individual sphingolipid activator proteins.
On the basis of Celtic habits Plinius has referred to the mistletoe as “omnia sanatem”. Another mythological source (the Baldur legend) describes the mistletoe as a deadly weapon. These roots, but not scientific reasoning have contributed to the introduction of mistletoe extracts to cancer treatment by R. Steiner in this century. Various products presently enjoy considerable popularity in Western Europe as an unconventional treatment modality. A scientific proof for the claimed clinical efficiency, however, has not been presented, justifying the sceptical judgement of the medical community. Explicit drawbacks to perform standard evaluation are the lack of precise definition of the concentrations of the various compounds in the commercially available extracts as well as of supposedly active substances and their doses to elicit potentially beneficial effects in patients. Prospective randomized trials with a well-characterized test substance that would separate wishful thinking from reality and facts can thus not be conducted. To establish the essential prerequisites for clinical studies, stepwise biochemical, cell biological and experimental animal studies have recently enabled to focus ensuing efforts on a mistletoe lectin. Based on in vitro and on in vivo experiments with animal tumor models the galactoside-specific lectin has been shown to be a biological response modifier. Although it should definitely not be overlooked that the lectin's immunomodulatory capacity has still to prove its clinical efficiency, this example shows that mythology can well prompt lectinological research with testable clinical impact.