Dual Mechanisms of ABCA1 Regulation by Geranylgeranyl Pyrophosphate

Xiaodong Gan,Rebecca Kaplan,John G Menke,Karen Macnaul,Yuli Chen,Carl P Sparrow,Gaochao Zhou,Samuel D Wright,Tian-Quan Cai

doi:10.1074/jbc.m109402200

Abstract

ATP-binding cassette transporter A1 (ABCA1) mediates an active efflux of cholesterol and phospholipids and is mutated in patients with Tangier disease. Expression of ABCA1 may be increased by certain oxysterols such as 22(R)-hydroxycholesterol via activation of the nuclear hormone receptor liver X receptor (LXR). In searching for potential modulators of ABCA1 expression, we have studied the effects of various mevalonate metabolites on the expression of ABCA1 in two human cell lines, THP-1 and Caco-2 cells. Most of the tested metabolites, including mevalonate, geranyl pyrophosphate, farnesyl pyrophosphate, and ubiquinone, failed to significantly change the expression levels of ABCA1. However, treatment with geranylgeranyl pyrophosphate resulted in a dose- and time-dependent reduction of ABCA1 expression. Geranylgeranyl pyrophosphate appears to reduce ABCA1 expression via two different mechanisms. One of these mechanisms is by acting directly as an antagonist of LXR since it reduces the interaction between LXR alpha or -beta with nuclear coactivator SRC-1. Another mechanism appears to involve activation of the Rho GTP-binding proteins since treatment of Caco-2 cells with inhibitors of geranylgeranyl transferase or the Rho proteins significantly increased the expression and promoter activity of ABCA1. Further studies showed that mutations in the DR4 element of the ABCA1 promoter completely eliminate the inducible activities of these inhibitors. These data indicate that activation of the Rho proteins may change the activation status of LXR.

Highlights

Plasma concentration of high density lipoprotein cholesterol is inversely related to the incidence of coronary heart disease (1, 2)
Our results suggest that ATP-binding cassette transporter A1 (ABCA1) and ABCG1 may be subjected to similar mechanisms of regulation by GGPP
Consistent with earlier reports (20, 21), we show that ABCA1 expression is effectively up-regulated by 22(R)-hydroxycholesterol, a product of the mevalonate biosynthetic pathway

Summary

Introduction

Plasma concentration of high density lipoprotein cholesterol is inversely related to the incidence of coronary heart disease (1, 2). Our understanding of the mechanisms that regulate HDL1 cholesterol has received a major advance with the elucidation of the cause of Tangier disease (TD). ABCA1 is a member of the ATP-binding cassette superfamily. These proteins couple the energy provided by ATP hydrolysis to the transport of a wide variety of molecules across membranes (8 –11). ABCA1 is thought to mediate the active efflux of cholesterol and phospholipids to apolipoprotein (apo) acceptors, most importantly apoA-I, the major apo of HDL (12, 13). Expression of ABCA1 is up-regulated by modified low density lipoprotein and down-regulated by HDL (17, 18). We found that geranylgeranyl pyrophosphate (GGPP), one of the major products of the mevalonate pathway, potently suppressed ABCA1 expression. We demonstrated that GGPP may regulate ABCA1 expression via two different mechanisms

Methods

Results

Conclusion