Human Acyl-CoA: Cholesterol Acyltransferase Inhibitory Activities of Aliphatic Acid Amides from Zanthoxylum piperitum DC.

Abstract

Acyl-CoA: cholesterol acyltransferase (ACAT) plays an important role in the esterification of cholesterol with its substrates, cholesterol and fatty acyl coenzyme A, to facilitate both intracellular storage and intercellular transport. ACAT-1 is more involved in macrophage foam cell formation and ACAT-2 plays a critical role in the cholesterol absorption process in intestinal enterocytes. Three aliphatic acid amides, β-sanshool (1), γ-sanshool (2), and hydroxy-β-sanshool (3), were isolated by bioassay-guided fractionation of the ethanolic extracts of Zanthoxylum piperitum DC. Compounds 1 and 2 inhibited human ACAT-1 and -2 activities with IC₅₀ values of 39.0 and 79.7 μM for 1 and of 12.0 and 82.6 μM for 2, respectively. However, the hACAT-1 and -2 inhibitory activities of compound 3 having hydroxyl group were relatively less than those of compounds 1 and 2. A semi-synthetic compound 4, which has acetyl residue at 2′-OH of compound 3, exhibited the increased hACAT-1 and -2 inhibitory activities with IC₅₀ values of 28.1 and 87.5 μM, respectively.