Retinoic acid increases the cellular cholesterol predominantly in a mTOR-independent manner

Retinoic acid (RA) plays a role in the mounting immune response and controls several functions of the human body, including cholesterol homeostasis. The synthesis, uptake, and efflux of cellular cholesterol are significantly linked to the mammalian target of rapamycin complex-1 (mTORC1). Activation of mTORC1 promotes the synthesis and uptake of the cholesterol and suppresses its efflux, thus causing accumulation of cellular cholesterol. It is intriguing to know the effect of a high dose of RA on cholesterol accumulation in macrophages (m phi) and whether it is via mTOR activation. It is important to note that the long-term treatment of RA in humans is safe. Therefore, we chose a high dose of RA to observe its effect, which may be implicated in diseases like visceral leishmaniasis, where cholesterol deficiency is established. In the present study, we found the increased expression of RAPTOR, a regulatory component of the mTORC1 complex, in m phi upon treatment with RA. We observed the increased expression of SREBP2, LDLR, and PCSK9 in RA-treated m phi under sufficient cholesterol conditions, which further increased cellular cholesterol levels. Notably, their expressions were decreased when the mTOR pathway was inhibited by rapamycin. However, treatment with rapamycin did not result in the loss of cellular cholesterol in RA-treated m phi. Comparison with rapamycin-treated m phi suggests that RA induces cellular cholesterol levels in a mTORC1-independent manner.

Automated summary

Retinoic acid (RA) activates mTORC1 complex, promoting cholesterol synthesis and uptake, and suppressing efflux, leading to cellular cholesterol accumulation. Increased expression of SREBP2, LDLR, and PCSK9 is associated with elevated cellular cholesterol levels induced by RA treatment, which is independent of mTORC1 activation.