Esterastin: A Potent Inhibitor of Lysosomal Acid Lipase1

Imanaka, Tsuneo; Moriyama, Yoshinori; Ecsedi, Gnobor G.; Aoyagi, Takaaki; Amanuma-Muto, Kimiko; Ohkuma, Shoji; Takano, Tatsuya

doi:10.1093/oxfordjournals.jbchem.a134399

Cited by 22 publications

(21 citation statements)

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“…6. Compound 3a1 is orlistat (tetrahydrolipstatin, Alli®, Xenical®), a well known inhibitor of various lipases, including LAL [59, 62]. Compound 3a8 is aurintricarboxylic acid, which has been reported to affect numerous cellular processes such as DNA replication [63] and apoptosis [64].…”

Section: Resultsmentioning

confidence: 99%

“…3A). One of these, compound 3a1, is tetrahydrolipstatin ((S)-((S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate), a well-characterized inhibitor of pancreatic lipase [62, 66–73] that can also inhibit other lipases [59, 62]. Another, compound 3a8, is aurintricarboxylic acid, which has been found to have numerous biological effects such as inhibition of translation initiation [74], DNA replication [63], apoptosis [64], and many others, but we are not aware of any prior reports of its inhibition of LAL or any other lipase.…”

Section: Discussionmentioning

confidence: 99%

“…There are other inhibitors of LAL ( e.g., tetrahydrolipstatin, or diethyl p- nitrophenyl phosphate (E600) [59, 62], and 4-PDMP (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol) [81]), but tetrahydrolipstatin and E600 also inhibit other lipases [66, 69, 70, 72, 82–84], whereas 4-PDMP was reported [81] to inhibit bis-(monoacylglycerol)-phosphate stimulation of LAL activity, but does not appear to have an effect in the absence of bis-(monoacylglycerol)-phosphate[21]. …”

Section: Discussionmentioning

confidence: 99%

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Chemical screen to reduce sterol accumulation in Niemann–Pick C disease cells identifies novel lysosomal acid lipase inhibitors

Rosenbaum

Rujoi

Huang

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SUMMARYNiemann-Pick C disease (NPC) is a lysosomal storage disorder causing abnormal accumulation of unesterified free cholesterol in lysosomal storage organelles. High content phenotypic microscopy chemical screens in both human and hamster NPC-deficient cells have identified several compounds that partially revert the NPC phenotype. Cell biological and biochemical studies show that several of these molecules inhibit lysosomal acid lipase, the enzyme that hydrolyzes LDL-derived triacylglycerol and cholesteryl esters. The effects of reduced lysosomal acid lipase activity in lowering cholesterol accumulation in NPC mutant cells were verified by RNAi-mediated knockdown of lysosomal acid lipase in NPC1-deficient human fibroblasts. This work demonstrates the utility of phenotypic cellular screens as a means to identify molecular targets for altering a complex process such as intracellular cholesterol trafficking and metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Chemical screen to reduce sterol accumulation in Niemann–Pick C disease cells identifies novel lysosomal acid lipase inhibitors

Rosenbaum

Rujoi

Huang

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…These are ebelactone, an inhibitor of pig liver esterase, pig pancreas lipase, and N-formyl-methionine aminopeptidase (31); and esterastin, which inhibited lysosomal acid lipase (32).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699.

Greenspan

Yudkovitz

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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“…Lipid droplets accumulated as membrane-free inclusion bodies even in the presence of esterastin, which is a lipase inhibitor (8,12,20,21). We discuss the possibility that lipid inclusion bodies are transferred to the cytoplasm from lysosomes after cholesteryl esters have been partially hydrolyzed.…”

mentioning

confidence: 95%

Intracellular transport of cholesteryl esters from lysosomes to cytoplasm in macrophages.

Mineo

Kanaseki

Enomoto

et al. 1988

Cell Struct. Funct.

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ABSTRACT. The mechanism through which nonmembranous lipid inclusion bodies consisting of cholesteryl esters accumulate in the cytoplasm was studied. Most lipid inclusion bodies in macrophages after 24 h incubation with anisotropic cholesteryl oleate liquid crystals were surrounded by a limiting membrane. The limiting membrane, however, could not be observed after further incubation for 48 h in the presence of esterastin, which is known to be an inhibitor of lipase and esterase. Under these conditions, the levels of hydrolysis and re-esterification of cholesteryl esters were less than 15% and 5% of the control ones, respectively.These results suggest that the inclusion bodies were transferred from lysosomes to the cytoplasm, with partial hydrolysis of cholesteryl esters, in addition to through the pathway via microsomes.A prominent feature of atherosclerosis is the marked accumulation of lipids, especially cholesteryl esters, in the arterial walls (15). These lipids are observed as small droplets showing intense anisotropy on polarized microscopy (5). They have been isolated (13,18), and their biochemical (13, 18) and morphological characteristics (1, 7, 13, 18) have been examined. They consist mainly of cholesteryl esters (about 95%) and have been called cholesteryl ester-rich lipid droplets (7). Some of the lipid-laden foam cells are thought to be derived from macrophages (11,17, 23). Histochemical and ultrastructural observations have showen that the lipid droplets, with or without a limiting membrane, mainly accumulate in the cytoplasm of foam cells in early atherosclerotic lesions (16). Studies involving the quick-freeze, etching technique (1) also showed that the lipids that accumulated in foam cells were present as membrane-bound droplets in lysosomes and as membrane-free droplets, with a concentric lamillar structure, surrounded by 10 nm filaments.When macrophages are incubated with acetyl-LDL (acetylated low density lipoprotein), the acetyl-LDL is internalized through endocytosis and then delivered to lysosomes (2, 6). Cholesteryl esters in the lipoprotein are hydrolyzed in lysosomes, and free cholesterol is liberated. According to the hypothesis of Brown et al. (2), the free cholesterol is re-esterified by a microsomal acyl-CoA: cholesterol Abbreviations used: acetyl-LDL, acetylated low density lipoprotein; PBS(-), Can-, Mg2+ free phosphate-buffered saline; ACAT, acyl-CoA: cholesterol acyltransferase. 435

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Esterastin: A Potent Inhibitor of Lysosomal Acid Lipase1

Cited by 22 publications

References 0 publications

Chemical screen to reduce sterol accumulation in Niemann–Pick C disease cells identifies novel lysosomal acid lipase inhibitors

Chemical screen to reduce sterol accumulation in Niemann–Pick C disease cells identifies novel lysosomal acid lipase inhibitors

Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699.

Intracellular transport of cholesteryl esters from lysosomes to cytoplasm in macrophages.

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