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. 2024 Mar 6;15:2058. doi: 10.1038/s41467-024-46315-7

Fig. 8. Proposed mechanism for DLAM response regulation by BHLHE40/41.

Fig. 8

Left) In wild-type mouse microglia or human iPSC-derived microglia (iMGLs) and THP-1 macrophages (MACs) treated with scrambled siRNA (and thus with normal levels of BHLHE40/41), when LXR:RXR and MiT/TFE family TFs stimulate the expression of cholesterol clearance and lysosomal processing genes that contribute to the LAM transcriptional program, they also stimulate the expression of BHLHE40 and BHLHE41. In turn, BHLHE40/41 oppose the activity of LXR:RXR and MiT/TFE family TFs by binding to the promoters of their target genes and leading to decreased expression of cholesterol clearance and lysosomal processing genes, in a negative feedback loop. Right) In mouse microglia or human iMGLs and MACs with complete loss or reduced levels of BHLHE40/41, this negative feedback loop is interrupted or weakened resulting in increased expression of cholesterol clearance and lysosomal processing genes to partially recapitulate the DLAM transcriptional and cellular response, including increased cholesterol efflux to APOE and storage in LDs, as well as increased lysosomal mass, acidification and proteolysis. The figure was created with BioRender.