Regulation of Lactosylceramide Biosynthesis: An Opportunity and a Challenge for Glycobiologists

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: glucosyl-ceramide,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 muscle cells, a hallmark in the pathophysiology in atherosclerosis. A.