EXOGENOUS AND ENDOGENOUS SOURCES OF STEROLS IN THE CULTURE-ADAPTED PROCYCLIC TRYPOMASTIGOTES OF TRYPANOSOMA-BRUCEI

The growth of the culture-adapted procyclic forms of Trypanosoma brucei (procyclics) is accelerated by supplementation of the medium with low-density Lipoprotein (LDL) particles. This effect can be attributed to receptor-mediated endocytosis of LDL, followed by utilization of lipids carried by the lipoproteins. Indeed, procyclics that normally contain ergosterol synthesized de novo, also incorporate exogenous cholesterol in their membranes. In turn, import of exogenous lipids down-regulates the isoprenoid biosynthetic machinery as measured by a approx. 3-fold decrease of [C-14]acetate incorporation into sterols and a approx. 2-fold decrease of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, compared with cells grown in lipoprotein-depleted medium. Synvinolin, a specific inhibitor of HMG-CoA reductase that slows down the procyclic growth in vitro and decreases [C-14]acetate incorporation into sterols, produces striking morphological modifications, including an arrest at cytokinesis and an extensive swelling of the kinetoplast-mitochondrion system. These cytotoxic effects are amplified in the absence of lipoprotein supply. In conclusion, procyclics may acquire sterols from both exogenous and endogenous sources. To a large extent, these two pathways compensate each other, illustrating adaptation of the parasites to survive in extremely different environments.