Orlistat Increases Arsenite Tolerance in THP-1 Derived Macrophages Through the Up-Regulation of ABCA1

Orlistat is an FDA-approved over-the-counter drug to treat obesity through the inhibition of lipase activity. Macrophages, which express high levels of lipoprotein lipase (LPL), are important phagocytes in the innate immune system. Our previous studies indicated that environmentally relevant concentrations of arsenite (As+3) could inhibit the major immune functions of macrophages. As the down-regulation of LPL is known to increase the expression of ABCA1, the cholesterol exporter demonstrated to be related to the resistance of arsenic toxicity. We examined if orlistat could reverse the inhibitive effects of As+3 on macrophage functions. The results showed that 50 mu M orlistat reversed As+3-induced suppressions on phagocytosis, NO production and cytokine secretion in THP-1 derived macrophages. The expression of ABCA1 was significantly increased by orlistat in As+3 co-treated macrophages, which was associated with decreased intracellular As+3 levels. Collectively, these results indicated that orlistat could reverse the suppressive effects induced by As+3 in macrophages through the increased expression of ABCA1, which has the potential to be developed as a therapeutic agent for arsenic-induced immunosuppression.