Sphingolipids have been accorded numerous biological functions however, the effects of feeding a western diet (diet rich in cholesterol and fat) on skin phenotypes, and color is not known. Here, we observed that chronic high-fat and high-cholesterol diet intake in a mouse model of atherosclerosis (ApoE-/-) decreases the level of ceramides and glucosylceramide. At the expense of increased levels of lactosylceramide due to an increase in the expression of lactosylceramide synthase (GalT-V). This is accompanied with neutrophil infiltration into dermis, and enrichment of tumor necrosis factor-stimulated gene-6 (TSG-6) protein. This causes skin inflammation, hair discoloration and loss, in ApoE-/- mice. Conversely, inhibition of glycosphingolipid synthesis, by D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), unbound or encapsulated in a biodegradable polymer (BPD) reversed these phenotypes. Thus, inhibition of glycosphingolipid synthesis represents a unique therapeutic approach relevant to human skin and hair Biology.