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Fig. 5 | Lipids in Health and Disease

Fig. 5

From: USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages

Fig. 5

Schematic presentation of the proposed mechanism for the effects of USF1 deficiency on cholesterol flux through a macrophage foam cell. Uptake of cholesteryl esters (CE) present in the core of modified LDL particles promotes the generation of macrophage foam cells. Modified LDL is taken up by scavenger receptors, such as SR-A1. Lack of USF1 resulted in reduced mRNA levels of SR-A1 and attenuated LPS-induced macrophage cholesterol deposition. Intracellular cholesterol flux-regulating enzymes, lysosomal acid lipase (LAL, gene name LIPA), acetyl-CoA cholesterol acyltransferase 1 (ACAT1) and neutral cholesterol ester hydrolase 1 (nCEH1) are key factors modulating macrophage cholesterol metabolism. Deficiency of Usf1 caused an upregulation in expression of NCEH1 and LIPA in both mouse peritoneal macrophages and human THP-1 cells, thereby enhancing intracellular cholesterol flux from lysosomes via CE droplets to plasma membrane. The protein expression of ABCA1, an important cholesterol transporter on macrophage plasma membrane, was also increased due to lack of USF1, further accelerating the removal of cholesterol to cholesterol acceptors (HDL), whose plasma levels were elevated in Usf1 deficient mice (16). The HDL particles derived from Usf1-/- mice had a higher proportion of phospholipids (PL) in HDL further explaining the elevated cholesterol acceptor capacity of Usf1-/- derived HDL particles. ABCA1 protein levels were upregulated in USF1 deficient hepatocytes, which may partially explain the elevated HDL levels in USF1 deficient mice. Expression of NF-κB, a key regulator of inflammation was decreased in peritoneal macrophages from USF1 deficient mice and, furthermore, secretion of cytokines (MCP-1 and IL-1β) was found to be decreased in USF1 silenced THP-1 macrophages. Arrows denote the effects of USF1 deficiency at relevant sites

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