LAL

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. In normal cells, LDL-associated cholesterol esters (CE) are transported via receptor-mediated endocytosis to the LE/LY. Within this compartment, lysosomal acid lipase (LAL) hydrolyzes CE to free cholesterol and fatty acids. Free cholesterol is then transported from the LE/LY to various organelles, including the endoplasmic reticulum (ER) and the plasmamembrane. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis[1]. On the other hand, Niemann-Pick type C disease is a rare, incurable, autosomal recessive lysosomal storage disorder. The disease is characterized by significant accumulation of unesterified cholesterol, glycosphingolipids, and other lipids within late endosomes/lysosomes (LE/LY)[2]. In sum, LAL represents a key protein controlling the availability of FC and FFAs, the building and energy blocks of cells. Thus, targeting lipid metabolism in immune cells may offer a therapeutic option for metabolic disorders such as dyslipidemia, and could potentially rewire the function of the immune system[1].


[1] M Gomaraschi et al. Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target. Trends Pharmacol Sci. 2019 Feb;40(2):104-115.
[2] AI Rosenbaum et al. Thiadiazole carbamates: potent inhibitors of lysosomal acid lipase and potential Niemann-Pick type C disease therapeutics. J Med Chem. 2010 Jul 22;53(14):5281-9.

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2797 Lalistat 2 Selective inhibitor of lysosomal acid lipase (LAL) €105.00

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