Regulation of ABCA1 in hepatocytes by the nuclear receptor PXR

Abstract

Abstract Nuclear receptors that work as heterodimers with RXR control several aspects of lipid metabolism. One such nuclear receptor, pregnane X receptor (PXR) is the molecular target for a wide variety of endogenous and xenobiotic compounds. PXR regulates the expression of genes central to the detoxification and excretion of potentially harmful compounds. Accumulation of intracellular cholesterol will lead to foam cell formation and necrosis if left unchecked. ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol from cells to apoA-I to produce HDL, which transports cholesterol to the liver for excretion. The aim of the present investigation was to determine the role of PXR in regulation of hepatic ABCA1 expression. Expression analyses were performed using Western blotting and quantitative real time RT-PCR. Luciferase reporter gene assays were used to measure promoter activities. Total cholesterol was measured enzymatically after lipid extraction (Folch’s method). The expression of ABCA1 was inhibited by the PXR activators rifampicin in HepG2 cells and pregnenolone 16á-carbonitrile (PCN) in primary rat hepatocytes and Hepa1c1c-7 cells. Thus, PXR appears to be a regulator of hepatic cholesterol transport. Keywords: ABCA1; PXR; Cholesterol; Liver