A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels.

Abstract

BACKGROUND:

Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role in foam cell formation in atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression of atherosclerosis is controversial.

METHODS AND RESULTS:

We developed and characterized a novel ACAT inhibitor, K-604. The IC(50) values of K-604 for human ACAT-1 and ACAT-2 were 0.45 and 102.85 micromol/L, respectively, indicating that K-604 is 229-fold more selective for ACAT-1. Kinetic analysis indicated that the inhibition was competitive with respect to oleoyl-coenzyme A with a K(i) value of 0.378 micromol/L. Exposure of human monocyte-derived macrophages to K-604 inhibited cholesterol esterification with IC(50) of 68.0 nmol/L. Furthermore, cholesterol efflux from THP-1 macrophages to HDL(3) or apolipoprotein A-I was enhanced by K-604. Interestingly, administration of K-604 to F1B hamsters on a high-fat diet at a dose of >or=1mg/kg suppressed fatty streak lesions without affecting plasma cholesterol levels.

CONCLUSIONS:

K-604, a potent and selective inhibitor of ACAT-1, suppressed the development of atherosclerosis in an animal model without affecting plasma cholesterol levels, providing direct evidence that pharmacological inhibition of ACAT-1 in the arterial walls leads to suppression of atherosclerosis.

• Authors: Mami Ikenoya, Yasunobu Yoshinaka, Hideyuki Kobayashi, Katsumi Kawamine, Kimiyuki Shibuya, Fumiyasu Sato, Kimio Sawanobori, Takuya Watanabe, Akira Miyazaki
• Journal: Atherosclerosis (Atherosclerosis) Vol. 191 Issue 2 Pg. 290-7 (Apr 2007) ISSN: 0021-9150 [Print] Ireland
• PMID: 16820149 (Publication Type: Journal Article)

Chemical References

• (2-(4-(2-benzimidazol-2ylthio)ethyl)piperazin-1yl)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide
• Benzimidazoles
• Dietary Fats
• Enzyme Inhibitors
• Cholesterol
• Sterol O-Acyltransferase
• sterol O-acyltransferase 1
• sterol O-acyltransferase 2

Topics

• Animals
• Atherosclerosis (chemically induced, metabolism, pathology, prevention & control)
• Benzimidazoles (pharmacology, therapeutic use)
• Binding, Competitive
• CHO Cells
• Cell Differentiation
• Cholesterol (blood, metabolism)
• Cricetinae
• Cricetulus
• Dietary Fats
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Esterification
• Humans
• Kinetics
• Macrophages (cytology, drug effects, metabolism)
• Male
• Monocytes (cytology)
• Sterol O-Acyltransferase (antagonists & inhibitors, genetics, metabolism)
• Transfection