Clofazimine Modulates the Expression of Lipid Metabolism Proteins in Mycobacterium leprae-Infected Macrophages

Abstract

Mycobacterium leprae (M. leprae) lives and replicates within macrophages in a foamy, lipid-laden phagosome. The lipids provide essential nutrition for the mycobacteria, and M. leprae infection modulates expression of important host proteins related to lipid metabolism. Thus, M. leprae infection increases the expression of adipophilin/adipose differentiation-related protein (ADRP) and decreases hormone-sensitive lipase (HSL), facilitating the accumulation and maintenance of lipid-rich environments suitable for the intracellular survival of M. leprae. HSL levels are not detectable in skin smear specimens taken from leprosy patients, but re-appear shortly after multidrug therapy (MDT). This study examined the effect of MDT components on host lipid metabolism in vitro, and the outcome of rifampicin, dapsone and clofazimine treatment on ADRP and HSL expression in THP-1 cells. Clofazimine attenuated the mRNA and protein levels of ADRP in M. leprae-infected cells, while those of HSL were increased. Rifampicin and dapsone did not show any significant effects on ADRP and HSL expression levels. A transient increase of interferon (IFN)-β and IFN-γ mRNA was also observed in cells infected with M. leprae and treated with clofazimine. Lipid droplets accumulated by M. leprae-infection were significantly decreased 48 h after clofazimine treatment. Such effects were not evident in cells without M. leprae infection. In clinical samples, ADRP expression was decreased and HSL expression was increased after treatment. These results suggest that clofazimine modulates lipid metabolism in M. leprae-infected macrophages by modulating the expression of ADRP and HSL. It also induces IFN production in M. leprae-infected cells. The resultant decrease in lipid accumulation, increase in lipolysis, and activation of innate immunity may be some of the key actions of clofazimine.

Mycobacterium lepraeintracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment

“…We and others have previously shown that the inhibition of LD formation in ML‐ and BCG‐infected cells reduces bacterial viability (D'Avila et al ., ; Almeida et al ., ; Mattos et al ., 2011b). Moreover, a recent report has suggested that clofazimine, one of the drugs that compose the WHO‐MDT regimen for leprosy treatment, exerts its microbicidal activity via the decreasing LD accumulation in infected cells (Degang et al ., ). Interestingly, besides its classical mechanistic action of inhibiting the HMGCR, lovastatin was able to decrease LDL‐Cho uptake in ML‐infected macrophages, corroborating with the literature data (Aviram et al ., ).…”

Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169)

“…BDQ is an inhibitor of the F 1 /F o ATP synthase, and CLO is thought to be reduced by the mycobacterial type 2 NADH:quinone oxidoreductase (NDH-2) enzyme, leading to a CLO-mediated increase in NADH oxidation and reactive oxygen species (ROS) production (12,13). Other studies have also reported that CLO may act on the lipids of the bacterial cell wall, as observed in macrophages infected with M. leprae (14). On the other hand, there were compounds targeting the ETC, such as LPZs, which were not synergistic when combined with MCZ in vitro (Table 3).…”

MALDI imaging reveals lipid changes in the skin of leprosy patients before and after multidrug therapy (MDT)

“…Besides ADRP and perlipin expression in infected cells, confirming the induction of lipid droplets in leprosy, it was shown that M. leprae ‐infected macrophages have a reduced expression of hormone‐sensitive lipase, which would help to increase intracellular lipid accumulation, favoring bacterial survival . Recently, a study on the influence of drugs used in leprosy MDT (dapsone, clofazimine and rifampicin) showed that clofazimine, but not dapsone or rifampicin, modulates lipid metabolism in infected THP‐1 cells, decreasing the expression of ADRP and increasing hormone‐sensitive lipase in M. leprae ‐infected cells . In the case of the patients studied in this work, all were submitted to standard MDT for multibacillary leprosy, which includes clofazimine.…”

“…[42,43] Recently, a study on the influence of drugs used in leprosy MDT (dapsone, clofazimine and rifampicin) showed that clofazimine, but not dapsone or rifampicin, modulates lipid metabolism in infected THP-1 cells, decreasing the expression of ADRP and increasing hormonesensitive lipase in M. leprae-infected cells. [44] In the case of the patients studied in this work, all were submitted to standard MDT for multibacillary leprosy, which includes clofazimine. Therefore, the lipid changes observed in the skin after treatment may be partially attributed to the effect of clofazimine on infected macrophages.…”