Selective inhibition of acyl coenzyme A

Cholesterol acyltransferase by compound 58-035

A. Catharine Ross, K. J. Go, J. G. Heider, G. H. Rothblat

Research output: Contribution to journalArticle

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Abstract

Compound 58-035 (3-[decyldimethylsily]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide) has been found to inhibit the accumulation of cholesteryl esters in both rat hepatoma (Fu5AH) cells and arterial smooth muscle cells in culture. To explore the specificity of 58-035, we have studied the esterification of cholesterol, retinol, and glycerides by the Fu5AH cell and by isolated membranes. Exposure of Fu5AH to cholesterol/phospholipid dispersions and 58-035 (> 100 ng/ml) for 24 h resulted in greater than 95% inhibition of cholesterol esterification while cellular free cholesterol increased slightly. Inhibition was also rapid; incorporation of [3H]oleate into cholesteryl [3H]oleate equaled only 12% of control value after 30 min with 58-035 at 5 μg/ml. In contrast, there was no decrease in [3H]oleate incorporation into phospholipids or diglycerides, nor was the esterification of [3H]retinol inhibited by 58-035. In microsomal fractions acyl-CoA:cholesterol acyltransferase could be inhibited completely by 58-035, while activities of acyl-CoA: retinol acyltransferase and triglyceride synthesis proceeded at 75-100% of control values. These observations that 58-035 is highly selective allow the inference that acyl-CoA:cholesterol acyltransferase is a separate microsomal enzyme whose activity can be modulated independently from acyl-CoA:retinol acyltransferase and other cellular acyltransferases.

Original languageEnglish (US)
Pages (from-to)815-819
Number of pages5
JournalJournal of Biological Chemistry
Volume259
Issue number2
StatePublished - 1984

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Sterol O-Acyltransferase
Acyl Coenzyme A
Retinol O-Fatty-Acyltransferase
Esterification
Oleic Acid
Cholesterol
Vitamin A
Phospholipids
Glycerides
Acyltransferases
Cholesterol Esters
Diglycerides
Enzyme activity
Dispersions
Cell culture
Smooth Muscle Myocytes
Muscle
Rats
Hepatocellular Carcinoma
Triglycerides

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ross, A. Catharine ; Go, K. J. ; Heider, J. G. ; Rothblat, G. H. / Selective inhibition of acyl coenzyme A : Cholesterol acyltransferase by compound 58-035. In: Journal of Biological Chemistry. 1984 ; Vol. 259, No. 2. pp. 815-819.
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abstract = "Compound 58-035 (3-[decyldimethylsily]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide) has been found to inhibit the accumulation of cholesteryl esters in both rat hepatoma (Fu5AH) cells and arterial smooth muscle cells in culture. To explore the specificity of 58-035, we have studied the esterification of cholesterol, retinol, and glycerides by the Fu5AH cell and by isolated membranes. Exposure of Fu5AH to cholesterol/phospholipid dispersions and 58-035 (> 100 ng/ml) for 24 h resulted in greater than 95{\%} inhibition of cholesterol esterification while cellular free cholesterol increased slightly. Inhibition was also rapid; incorporation of [3H]oleate into cholesteryl [3H]oleate equaled only 12{\%} of control value after 30 min with 58-035 at 5 μg/ml. In contrast, there was no decrease in [3H]oleate incorporation into phospholipids or diglycerides, nor was the esterification of [3H]retinol inhibited by 58-035. In microsomal fractions acyl-CoA:cholesterol acyltransferase could be inhibited completely by 58-035, while activities of acyl-CoA: retinol acyltransferase and triglyceride synthesis proceeded at 75-100{\%} of control values. These observations that 58-035 is highly selective allow the inference that acyl-CoA:cholesterol acyltransferase is a separate microsomal enzyme whose activity can be modulated independently from acyl-CoA:retinol acyltransferase and other cellular acyltransferases.",
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Selective inhibition of acyl coenzyme A : Cholesterol acyltransferase by compound 58-035. / Ross, A. Catharine; Go, K. J.; Heider, J. G.; Rothblat, G. H.

In: Journal of Biological Chemistry, Vol. 259, No. 2, 1984, p. 815-819.

Research output: Contribution to journalArticle

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T1 - Selective inhibition of acyl coenzyme A

T2 - Cholesterol acyltransferase by compound 58-035

AU - Ross, A. Catharine

AU - Go, K. J.

AU - Heider, J. G.

AU - Rothblat, G. H.

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N2 - Compound 58-035 (3-[decyldimethylsily]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide) has been found to inhibit the accumulation of cholesteryl esters in both rat hepatoma (Fu5AH) cells and arterial smooth muscle cells in culture. To explore the specificity of 58-035, we have studied the esterification of cholesterol, retinol, and glycerides by the Fu5AH cell and by isolated membranes. Exposure of Fu5AH to cholesterol/phospholipid dispersions and 58-035 (> 100 ng/ml) for 24 h resulted in greater than 95% inhibition of cholesterol esterification while cellular free cholesterol increased slightly. Inhibition was also rapid; incorporation of [3H]oleate into cholesteryl [3H]oleate equaled only 12% of control value after 30 min with 58-035 at 5 μg/ml. In contrast, there was no decrease in [3H]oleate incorporation into phospholipids or diglycerides, nor was the esterification of [3H]retinol inhibited by 58-035. In microsomal fractions acyl-CoA:cholesterol acyltransferase could be inhibited completely by 58-035, while activities of acyl-CoA: retinol acyltransferase and triglyceride synthesis proceeded at 75-100% of control values. These observations that 58-035 is highly selective allow the inference that acyl-CoA:cholesterol acyltransferase is a separate microsomal enzyme whose activity can be modulated independently from acyl-CoA:retinol acyltransferase and other cellular acyltransferases.

AB - Compound 58-035 (3-[decyldimethylsily]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide) has been found to inhibit the accumulation of cholesteryl esters in both rat hepatoma (Fu5AH) cells and arterial smooth muscle cells in culture. To explore the specificity of 58-035, we have studied the esterification of cholesterol, retinol, and glycerides by the Fu5AH cell and by isolated membranes. Exposure of Fu5AH to cholesterol/phospholipid dispersions and 58-035 (> 100 ng/ml) for 24 h resulted in greater than 95% inhibition of cholesterol esterification while cellular free cholesterol increased slightly. Inhibition was also rapid; incorporation of [3H]oleate into cholesteryl [3H]oleate equaled only 12% of control value after 30 min with 58-035 at 5 μg/ml. In contrast, there was no decrease in [3H]oleate incorporation into phospholipids or diglycerides, nor was the esterification of [3H]retinol inhibited by 58-035. In microsomal fractions acyl-CoA:cholesterol acyltransferase could be inhibited completely by 58-035, while activities of acyl-CoA: retinol acyltransferase and triglyceride synthesis proceeded at 75-100% of control values. These observations that 58-035 is highly selective allow the inference that acyl-CoA:cholesterol acyltransferase is a separate microsomal enzyme whose activity can be modulated independently from acyl-CoA:retinol acyltransferase and other cellular acyltransferases.

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