Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

León, Carlos; Hill, John S.; Wasan, Kishor M.

doi:10.1007/s11095-005-6306-0

Cited by 71 publications

(61 citation statements)

References 109 publications

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“…ACAT1 is of particular interest, as it was found to be significantly elevated in prostate cancer metastatic lesions. ACAT1 inhibitors have been previously investigated for various other diseases (58,59) and present an interesting avenue of therapeutic intervention to potentially treat high-grade and metastatic prostate cancers.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression

Saraon

Creţu

Musrap

et al. 2013

Molecular & Cellular Proteomics

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Prostate cancer is the most common malignancy and the second leading cause of cancer-related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumors that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line and its androgen-independent derivative, LNCaP-SF. Utilizing stable isotope labeling with amino acids in cell culture coupled to mass spectrometry, we assessed the differential global protein expression of the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins. Bioinformatic prioritization resulted in 42 up-regulated and 46 down-regulated proteins in LNCaP-SF cells relative to LNCaP cells. Our top candidate, HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, and OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells, which was further verified using Western blotting. To determine whether these enzymes were up-regulated in clinical samples, we performed quantitative PCR and immunohistochemistry on human prostate cancer tissues, from which we observed significantly increased transcript and protein levels in high-grade cancer (Gleason grade > 8). In addition, we observed significant elevation of these enzymes in the LuCaP 96AI castration-resistant xenograft. Further assessment of ACAT1 on human castration-resistant metastatic prostate cancer tissues revealed substantially elevated expression of ACAT1 in these specimens. Taken together, our results indicate that enzymes of the ketogenic pathway are up-regulated in high-grade prostate cancer and could serve as potential tissue

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Section: Discussionmentioning

confidence: 99%

Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression

Saraon

Creţu

Musrap

et al. 2013

Molecular & Cellular Proteomics

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“…ACAT is an integral membrane protein localized in the endoplasmic reticulum and it is important in catalyzing the transfer of cholesterol to cholesterol esters [2,22]. These cholesterol esters are further stored as lipid droplets within the cell.…”

Section: Introductionmentioning

confidence: 99%

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

et al. 2007

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BACKGROUND. The objective of this work was to determine the effect of an androgen agonist, R1881, on intracellular cholesterol synthesis and esterification in androgen-sensitive (AS) prostate cancer (LNCaP) cells. METHODS. We investigated the activity and expression of cholesterol metabolism enzymes, HMG-CoA-reductase and ACAT in the LNCaP and PC-3 (androgen-independent control) models. RESULTS. Microsomal PC-3 HMG-CoA-reductase activity was increased with R1881 despite having similar cholesterol levels while increased cholesterol levels in microsomes from LNCaPs treated with R1881 (Lþ) were associated with increased HMG-CoA reductase activity. Increased intracellular cholesteryl esters (CE) found in (Lþ) were not associated with an increased ACAT1 activity. There was no effect from androgen treatment on ACAT1 protein expression in theses cells; however, ACAT2 expression was induced upon R1881 treatment. In contrast, we found an increase in the in vitro ACAT1 activity in PC-3 cells treated with androgen (Pþ). Only ACAT1 expression was induced in Pþ. We further assessed the expression of STAT1a, a transcriptional activator that modulates ACAT1 expression. STAT1a expression and phosphorylation were induced in Pþ. To determine the role of the AR on ACAT1 expression and esterification, we treated PC-3 cells overexpressing the androgen receptor with R1881 (PARþ). AR expression was decreased in PARþ cells; ACAT1 protein expression and cholesterol ester levels were also decreased, however, ACAT2 remained unchanged. STAT1a expression was decreased in PARþ. CONCLUSIONS. Overall, these findings support the importance of cholesterol metabolism regulation within prostate cancer cells and unravel a novel role for STAT1a in prostate cancer metabolism.

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“…The transport of CE by LDL from the liver to peripheral cells and hydrolysis by LCAT are critical events for the homeostasis of cholesterol in the intact animal. The important role played by these enzymes is also recognized as a potential pharmaceutical target for diseases such as atherosclerosis (10,11). There have been several approaches to quantitate molecular species of neutral lipids, exemplified by TAG at the individual molecular species level, using techniques such GC-MS, atmospheric pressure chemical ionization, and ESI (12).…”

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confidence: 99%

Separation of cellular nonpolar neutral lipids by normal-phase chromatography and analysis by electrospray ionization mass spectrometry

Hutchins

Barkley

Murphy

2008

Journal of Lipid Research

116

104

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Neutral lipids are an important class of hydrophobic compounds found in all cells that play critical roles from energy storage to signal transduction. Several distinct structural families make up this class, and within each family there are numbers of individual molecular species. A solvent extraction protocol has been developed to efficiently isolate neutral lipids without complete extraction of more polar phospholipids. Normal-phase HPLC was used for the separation of cholesteryl esters (CEs), monoalkylether diacylglycerols, triacylglycerols, and diacylglycerols in a single HPLC run from this extract. Furthermore, minor lipids such as ubiquinone-9 could be detected in RAW 264.7 cells. Molecular species that make up each neutral lipid class can be analyzed both qualitatively and quantitatively by on-line LC-MS and LC-MS/MS strategies. The quantitation of .20 CE molecular species revealed that challenging RAW 264.7 cells with a Toll-like receptor 4 agonist caused a .20-fold increase in the content of CEs within cells, particularly those CE molecular species that contained saturated (14:0, 16:0, and 18:1) fatty acyl groups. Longer chain CE molecular species did not change in response to the activation of these cells.-Hutchins, P. M., R. M. Barkley, and R. C. Murphy. Separation of cellular nonpolar neutral lipids by normal-phase chromatography and analysis by electrospray ionization mass spectrometry. J. Lipid Res. 2008. 49: 804-813.

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Potential Role of Acyl-Coenzyme A:Cholesterol Transferase (ACAT) Inhibitors as Hypolipidemic and Antiatherosclerosis Drugs

Cited by 71 publications

References 109 publications

Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression

Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

Separation of cellular nonpolar neutral lipids by normal-phase chromatography and analysis by electrospray ionization mass spectrometry

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