Facile method to incorporate high-affinity ACAT/SOAT1 inhibitor F12511 into stealth liposome-based nanoparticle and demonstration of its efficacy in blocking cholesteryl ester biosynthesis without overt toxicity in neuronal cell culture

Torre, Adrianna L. De La; Smith, C G; Granger, Joseph E.; Anderson, Faith L; Harned, Taylor C.; Havrda, Matthew C.; Chang, Catherine C.Y.; Chang, Ta−Yuan

doi:10.1016/j.jneumeth.2021.109437

Cited by 5 publications

(13 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For treating NPCD, however, an important preclinical evaluation will be to test their brain permeability in animal models. We are currently developing methods ( 67 ) to deliver brain-permeable ACAT inhibitors to young mutant NPC1 mice on a daily basis. On the longer time horizon, ACAT inhibitors will require testing in NPC patients without deficiency in the cellular cholesterol efflux process.…”

Section: Discussionmentioning

confidence: 99%

Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells

Rogers

Chang

Maue

et al. 2022

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

Self Cite

View full text Add to dashboard Cite

Significance Niemann-Pick type C disease (NPCD) is an incurable genetic neurological disorder. Cells with NPC mutations fail to export cholesterol from endosomal organelle to multiple other organelles. ACAT1 is an enzyme that converts cholesterol to cholesteryl esters for storage. In mutant NPC cells, cholesterol storage still occurs, although at reduced rate. Here we show that in mutant NPC cells, ACAT1 blockade (A1B) decreases cholesterol storage such that it can be utilized to fulfill cholesterol needs in multiple organelles. In mutant NPC1 mice, Acat1 gene knockout reduces pathological onset and prolongs the lifespan by 34%. This work identifies ACAT1 as a target to treat NPCD and may help to explain why A1B has been reported to ameliorate preclinical models for Alzheimer’s disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells

Rogers

Chang

Maue

et al. 2022

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar experiments were performed with another ACAT1/SOAT1 inhibitor: F12511. The results showed that F12511 could not easily wash out of cells; a pre-treatment with this compound strongly inhibits ACAT activity after 8 h of repeated washing [ 71 ]. We attribute this to F12511′s higher binding affinity, and the fact that it is much more hydrophobic and cannot be removed from the membrane easily.…”

Section: Resultsmentioning

confidence: 99%

Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity

Harned

Stan

Cao

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer’s disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain unknown. Here, using biochemical fractionation techniques, we observe cholesterol accumulation at the MAM which leads to ACAT1/SOAT1 enrichment in this domain. MAM proteomics data suggests that ACAT1/SOAT1 inhibition strengthens the ER-mitochondria connection. Confocal and electron microscopy confirms that ACAT1/SOAT1 inhibition increases the number of ER-mitochondria contact sites and strengthens this connection by shortening the distance between these two organelles. This work demonstrates how directly manipulating local cholesterol levels at the MAM can alter inter-organellar contact sites and suggests that cholesterol buildup at the MAM is the impetus behind the therapeutic benefits of ACAT1/SOAT1 inhibition.

show abstract

“…Incorporating the potent hydrophobic SOAT inhibitor F12511 as stealth liposomes with DSPE-PEG 2000 and egg phosphatidiylcholine in ethanol resulted in a nanoparticle (nanoparticle F). This nanoparticle showed efficacy in the inhibition of SOAT in human and mouse neuronal and microglial cell lines with minimal toxicity and thus offers a promising route for the drug delivery of hydrophobic SOAT inhibitors …”

Section: Critical Discussion and Conclusionmentioning

confidence: 99%

“…This nanoparticle showed efficacy in the inhibition of SOAT in human and mouse neuronal and microglial cell lines with minimal toxicity and thus offers a promising route for the drug delivery of hydrophobic SOAT inhibitors. 212 Though the clinical development of "imibes" (avasimibe, pactimibe and eflucimibe) was discontinued, the combination therapy of SOAT inhibitors with statins or similar agents may offer synergism in ameliorating atherosclerotic lesions and modulating cholesterol. Over the past few years, emerging research on SOAT inhibitors has been more intriguing and encouraging to the point where this target has hopes of being revived.…”

Section: Critical Discussion and Conclusionmentioning

confidence: 99%

Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential

2022

View full text Add to dashboard Cite

Sterol O-acyltransferase (SOAT) is a membrane-bound enzyme that aids the esterification of cholesterol and fatty acids to cholesterol esters. SOAT has been studied extensively as a potential drug target, since its inhibition can serve as an alternative to statin therapy. Two SOAT isozymes that have discrete functions in the human body, namely, SOAT1 and SOAT2, have been characterized. Over three decades of research has focused on candidate SOAT1 inhibitors with unsatisfactory results in clinical trials. Recent research has focused on targeting SOAT2 selectively. In this perspective, we summarize the literature covering various SOAT inhibitory agents and discuss the design, structural requirements, and mode of action of SOAT inhibitors.

show abstract

Facile method to incorporate high-affinity ACAT/SOAT1 inhibitor F12511 into stealth liposome-based nanoparticle and demonstration of its efficacy in blocking cholesteryl ester biosynthesis without overt toxicity in neuronal cell culture

Cited by 5 publications

References 54 publications

Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells

Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells

Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity

Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential

Contact Info

Product

Resources

About