Acetyl-CoA acetyltransferase 1 (ACAT 1) is a protein coding gene that encodes a nitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA rom two molecules of acetyl-CoA. This enzyme plays an essential role in breaking down proteins and fats from diet. it helps process isoleucine, an amino acid that is a building block of many proteins. This enzyme is also involved in processing ketones, which are molecules that are produced when fats are broken down in the body.
K-604 dihydrochloride is a potent and selective acyl-CoA:cholesterol acyltransferase 1 (ACAT-1) inhibitor with an IC50 of 0.45±0.06 μM. K-604 efficiently inhibits cholesterol esterification in human macrophages with IC50 value of 68 nM. The plasma cholesterol levels in fat-fed hamsters are ~12-fold higher than those in chow-fed hamsters, which are significantly decreased by K-604 only at the highest dose tested (30 mg/kg) but not at lower doses (1-10 mg/kg). The fatty streak lesions stain with oil red O are markedly induced by the high-fat diet, which is significantly reduced by administration of K-604.[1]. Administration of K-604 to 8-week-old apoE-knockout mice for 12 weeks at a dose of 60 mg/kg/day significantly reduced macrophage-positive area and increased collagen-positive area in atherosclerotic plaques in the aorta without affecting plasma cholesterol levels or lesion areas, indicating direct plaque-modulating effects of K-604 on vascular walls independent of plasma cholesterol levels. Exposure of cultured human aortic smooth muscle cells to K-604 resulted in increased procollagen type 1 contents in the culture supernatant and increased procollagen type 1 mRNA levels[2].
K-604 2HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HMC3 cells
0.5 µM
4 hours
Measure ACAT activity and observe cholesterol accumulation around ACAT1/SOAT1 after K-604 treatment
Int J Mol Sci. 2023 Mar 14;24(6):5525
CHO cells
0.5 µM
4 hours
Measure ACAT activity and observe cholesterol accumulation around ACAT1/SOAT1 after K-604 treatment
Int J Mol Sci. 2023 Mar 14;24(6):5525
SHSY5Y cells
0.5 µM
4 hours
Measure ACAT activity and observe cholesterol accumulation around ACAT1/SOAT1 after K-604 treatment
Int J Mol Sci. 2023 Mar 14;24(6):5525
N9 cells
0.5 µM
4 hours
Measure ACAT activity and observe cholesterol accumulation around ACAT1/SOAT1 after K-604 treatment
Int J Mol Sci. 2023 Mar 14;24(6):5525
rat brain capillary endothelial cells
1 μM
30 minutes
Evaluate the BBB permeability of K-604. Results showed that the apparent permeability coefficient (Papp) of K-604 (21.9 × 10−6 cm/s) was lower than that of carbamazepine (47.8 × 10−6 cm/s).
ACS Omega. 2019 Oct 2;4(16):16943-16955
N9 microglial cells
0.5 µM
4 hours
K-604 significantly reduced LPS-induced pro-inflammatory gene expressions and increased TLR4 endocytosis, thereby enhancing TLR4 trafficking to lysosomes for degradation.
Int J Mol Sci. 2023 Mar 15;24(6):5616
Primary cortical neurons
0.5 µM
24 hours
K604 reduced P301L-tau protein levels and increased LC3-II levels, indicating enhanced autophagosome formation.
Neurobiol Aging. 2015 Jul;36(7):2248-2259
Mouse neuroblastoma cell line N2a
0.1 to 1 µM
24 hours
K604 at 0.1 to 1 µM inhibited ACAT activity by 60-80% and increased the LC3-II/LC3-I ratio, indicating enhanced autophagosome formation.
Evaluate the efficiency of K-604 delivery to the brain via intranasal administration. Results showed that the brain AUC after intranasal administration was 133-fold higher than that after oral administration, and the level of cholesteryl esters in the brain significantly decreased after 7 days of administration.
ACS Omega. 2019 Oct 2;4(16):16943-16955
C57BL6/J mice
Intratracheal bleomycin-induced acute lung injury model
Intratracheal administration
10 mg/kg
Administered on day 0 and day 3, sacrificed on day 7
K-604 reduced bleomycin-induced alveolar thickening, decreased inflammatory response and macrophage activation, and improved surfactant composition.
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