Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function?

Abstract

Apolipoprotein J (apo J) is a secreted glycoprotein of which the exact function remains a matter for speculation. Apo J has been implicated in such diverse processes as sperm maturation, regulation of complement activation, programmed cell death, tissue remodelling and lipid transport. In this study a possible role for apo J in lipid transport was explored. Mouse peritoneal macrophages were incubated with acetylated low-density lipoprotein (AcLDL) to produce foam cells containing cholesterol and cholesteryl esters. Incubation of the foam cells with physiological concentrations of purified apo J led to a dose-dependent export of cholesterol. The appearance of cholesterol in the medium was associated predominantly with a decline in intracellular cholesteryl esters rather than intracellular free cholesterol. The kinetics of cholesterol release to apo J were similar to apo A-I, an established promoter of cholesterol efflux. Apo J was also shown to induce phospholipid efflux from cells, whereas the cholesterol exported to the medium was associated with the apo J. Studies using foam cells from apo E-null mice showed that the cholesterol exported to the medium was independent of apo E production by the cells. These results present the first evidence that apo J can promote cholesterol efflux from foam cells and indicates that it might have a function in cellular cholesterol homoeostasis in both normal and pathological situations.

Serum Apolipoprotein J in Health, Coronary Heart Disease and Type 2 Diabetes Mellitus

“…Apo J is present in human and mouse atherosclerotic lesions, but not in normal arterial tissue 10,11) . In tissue culture, it acts as an acceptor of cholesterol from macrophage-derived foam cells 3) . It also regulates the proliferation, differentiation and migration of vascular smooth muscle cells 12,13) .…”

“…It is a disulfide-linked heterodimer composed of and subunits, generated by a single cleavage in the single-chain precursor protein 1,2) . It is ubiquitously expressed in many tissues, and binds to many biological molecules, including lipids 3) , apo A- 4) , paraoxonase 5) and gp330 (low-density lipoprotein [LDL] receptor-related protein) 6) . It exists in plasma as a component of a lipid-poor subclass of high-density lipoproteins (HDLs) of molecular mass 70-200 kDa [7][8][9] .…”

Clusterin mRNA expression in apoptotic and activated rat thymocytes

“…While its biological role is still under dispute, a variety of putative functions have been suggested. These include a role in serving as a lipid transport molecule [4], a regulator of complement-mediated cytolysis [5] as well as a playing role in the protection of the cell membrane from stress by acting as a secreted heat shock protein [6] or involvement in the cellular response upon apoptosis [7]. Such variant functional roles have lead to reporting the same protein under several different names, which include sulfated glycoprotein-2 (sgp-2) [8], ionizing radiationinduced protein-8 (XIP8), testosterone-repressed prostate message-2 (TRPM-2) as well as clusterin and Apo/J.…”

Nerve growth factor and epidermal growth factor stimulate clusterin gene expression in PC12 cells

“…Human clusterin was detected in all body fluids that have been investigated, including serum, where the protein is found as part of the high-density lipoprotein fraction [1][2][3][4][5]. Clusterin is synthesized at an elevated level during a number of physiological processes such as development and differentiation, and in various pathological disorders [3,6,7].…”

“…A recent study demonstrates an active function of clusterin in the reverse transport of cholesterol by stimulating its export from macrophage cells [5], a process that could have a role in counteracting the fatal role of foam-cell macrophages in the formation of atherosclerotic plaques. Reverse cholesterol transport from peripheral cells could also be a key function of the protein in apoptotic tissues, where the surviving cells that phagocytose the dead cell remnants accumulate cholesterol.…”