Retinoic acid restores the levels of cellular cholesterol in Leishmania donovani infected macrophages by increasing npc1 and npc2 expressions

Retinoic Acid Increases Cellular Cholesterol in Leishmania donovani-Infected Macrophages in an mTOR-Independent Manner

“…This results in poor immune responses in infected macrophages (Mϕ) showing increased expression of arginase-1 and interleukin 10 (IL-10). Our recent findings also show that RA restores the cellular cholesterol by increasing its lysosomal uptake (via NPC-1 and NPC-2 proteins) in L. donovani -infected Mϕ ( 6 ). In extrahepatic cells such as Mϕ, cellular cholesterol is maintained in three possible ways; synthesis, uptake, and efflux.…”

“…We have already demonstrated that RA increases the mRNA expression of npc-1 and npc-2 genes, which are involved in lysosomal transfer of cholesterol, and restores expression in L. donovani -infected Mϕ ( 6 ). Since we observed decreases in the mRNA expression of RAPTOR and SREBP2 genes in L. donovani -infected Mϕ, we measured the levels of these genes after treating the infected cells with RA.…”

“…In general, it is believed that RA, an active metabolite of vitamin A, performs various biological functions, including immune response regulation through interaction with retinoic acid response element (RARE)-binding receptors. Our findings showed the presence of RARE sites upstream of npc-1 and npc-2 genes, which are involved in lysosomal uptake of cholesterol ( 6 ). Interestingly, we have also shown that RA exerts its effect on cellular cholesterol level in an mTORC1 (mammalian [or mechanistic] target of rapamycin complex 1)-dependent manner in Mϕ.…”

“…We have shown here that L. donovani infection reduces this significant transcription factor in Mϕ, which possibly impairs the expression of HMGCR , LDLR , and ABCA1 . We have already shown that the L. donovani infection decreases the levels of cellular cholesterol in Mϕ by impairing the mRNA expression of npc-1 and npc-2 ( 6 ). In the same study, we showed improvement in the levels of cellular cholesterol in L. donovani -infected Mϕ upon RA treatment, which resulted in reduced parasite burden ( 6 ).…”

“…We have already shown that the L. donovani infection decreases the levels of cellular cholesterol in Mϕ by impairing the mRNA expression of npc-1 and npc-2 ( 6 ). In the same study, we showed improvement in the levels of cellular cholesterol in L. donovani -infected Mϕ upon RA treatment, which resulted in reduced parasite burden ( 6 ). In another part of our study in healthy uninfected Mϕ, RA was shown to restore the levels of cellular cholesterol in an mTOR-independent manner ( 9 ).…”