Cultured gallbladder epithelial cells synthesize apolipoproteins A-I and E

Abstract

Gallbladder epithelial cells (GBEC) are exposed to high and fluctuating concentrations of biliary cholesterol on their apical (AP) surface. GBEC absorb and efflux cholesterol, but the mechanisms of cholesterol uptake, intracellular trafficking, and efflux in these cells are not known. We previously reported that ATP binding cassette (ABC)A1 mediates basolateral (BL) cholesterol efflux in cultured polarized GBEC. In addition, the nuclear hormone receptors liver X receptor (LXR)α and retinoid X receptor (RXR) mediate both AP and BL cholesterol efflux. An interesting finding from our previous study was that apolipoprotein (apo)A-I applied to the AP surfaces of cells elicited BL ABCA1-mediated cholesterol efflux. Because ABCA1-mediated cholesterol efflux requires the presence of a cholesterol acceptor, we hypothesized that GBEC synthesize and secrete endogenous apo into the BL compartment. Here, we demonstrate that cholesterol loading of cells with model bile and AP apoA-I treatment is associated with an increase in the synthesis of apoE mRNA and protein. Furthermore, apoE is secreted into the BL compartment. LXRα/RXR ligands stimulate the synthesis of endogenous apoA-I mRNA and protein, as well as apoE mRNA. BL secretion of apoA-I is elicited by LXRα/RXR ligands. Therefore, GBEC synthesize apoA-I and -E and efflux cholesterol using ABCA1- and non-ABCA1- mediated pathways. These processes may alter gallbladder biliary cholesterol concentrations and thereby influence gallstone formation.

HMG-CoA Reductase Inhibitors (Statins) Activate Expression of PPARα/PPARγ and ABCA1 in Cultured Gallbladder Epithelial Cells

“…This, in turn, leads to increased PPARc activity, enhanced LXR activation, increased ABCA1 expression, and cholesterol efflux [49]. We have also suggested that an ABCA1-LXRa/RXRmediated cholesterol efflux system in GBEC may be a key defense mechanism for preventing chronic inflammation and loss of motility in the GB [9,10]. We propose that statin-induced activation of ABCA1 expression via the LXRa-mediated pathway can play a role in eliminating excessively loaded cholesterol in GBEC.…”

“…PPARa and PPARc are also known to activate ABCA1, the major cholesterol efflux transporter in peripheral cells, through LXRa/RXR stimulation, which are regulatory nuclear hormone receptors, in various cells [6][7][8]. Earlier, we showed that PPARa and PPARc ligands activate ABCA1 by an LXRa-mediated pathway in GBEC [5], and that GBEC eliminate excessive cholesterol by means of the LXRa/RXR-ABCA1-mediated cholesterol efflux system [9,10].…”

Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids

“…This latter process may involve megalin/cubilin-mediating lipid absorption/ transport processes via the uptake of lipoproteins such as apoA-I. ApoA-I is secreted by GBECs (52,58) as well as apoE, another lipid transport protein that is a megalin ligand. ApoJ has a high affinity for megalin (53) that is increased after the association with lipids, and we find it expressed and secreted by GBECs, consistent with the in situ hybridization data of others (65).…”

The Neglected Cousin of the Hepatocyte: How Gallbladder Epithelial Cells Might Contribute to Cholesterol Gallstone Formation

“…In the isolated normal human perfused gallbladder, addition of HDL to the arterial perfusate efficiently mobilizes cholesterol from the gallbladder [18]. However, gallbladder epithelial cells express and secrete apolipoprotein (apo)A-I and apoE [19]. The expression of apoA-I suggests the possibility that gallbladder epithelial cells export cholesterol in the form of HDL particles, potentially representing a novel cell type in addition to hepatocytes and enterocytes that can form HDL.…”