Atherosclerosis is a chronic disease of the arterial wall, characterized by the development of lipid-rich plaques. Cholesterol absorption and excretion pathways are therefore of great interest. Since the intestine is a major interface in cholesterol turnover, it represents a pharmacologically interesting target tissue.
To assess the influence of natural products on cholesterol uptake, a human intestinal cell model utilizing a monolayer of polarised Caco-2 cells has been established. After treating the monolayer with compounds (48 h), micelles with radioactively labelled cholesterol are added for two hours. Then, cells are lysed and intracellular cholesterol is quantified.
A major regulator of cholesterol homeostasis is the nuclear receptor LXR (liver X receptor). Several cholesterol transporters, like ABCA1 (ATP-binding cassette transporter A1), are regulated by this nuclear receptor. A piperine derivative (LAU398, Figure 1) upregulated ABCA1 in THP-1-derived macrophages (EC50 of 4.1 µM) and increased cholesterol efflux (EC50 of 1.1 µM) in this cell line. Hence, LAU398 was further investigated in cholesterol uptake experiments in intestinal cells. At 10 µM, LAU398 significantly reduced the uptake of cholesterol into Caco-2 cells. Interestingly, LAU398 also significantly enhanced capsaicin-induced currents through TRPV1 channels at 100 µM in oocytes [1]. However, co-administration with a TRPV1 or LXR antagonist could not reverse the effects of LAU398 on cholesterol uptake.
In conclusion, LAU398 significantly reduces cholesterol uptake in Caco-2 cells and enhances cholesterol efflux from THP-1-derived macrophages. The exact implications of TRPV1 or nuclear receptors in these effects remain to be elucidated.
Figure 1: Structure of the piperine derivative LAU398.
[1] Wimmer, L, Schonbauer, D, Pakfeifer, P, Schoffmann, A, Khom, S, Hering, S, and Mihovilovic, M D. Org Biomol Chem 2015; 13: 990-994