Intracellular cholesterol mobilization involved in the ABCA1/apolipoprotein-mediated assembly of high density lipoprotein in fibroblasts

• Published in: Journal of lipid research Vol. 45; no. 10; pp. 1943 - 1951
• Main Authors: Yamauchi, Yoshio, Chang, Catherine C.Y., Hayashi, Michi, Abe-Dohmae, Sumiko, Reid, Patrick C., Chang, Ta-Yuan, Yokoyama, Shinji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2004; Elsevier
• Subjects: acyl-coenzyme A:cholesterol acyltransferase; Animals; apolipoprotein A-I; Apolipoprotein A-I - metabolism; Apolipoproteins - metabolism; ATP Binding Cassette Transporter 1; ATP binding cassette transporter A1; ATP-Binding Cassette Transporters - metabolism; Biological Transport; Cell Line; Cholesterol - metabolism; Enzyme Activation; Fibroblasts - metabolism; Humans; Lipoproteins, HDL - metabolism; protein kinase C; Protein Kinase C - metabolism; Sterol O-Acyltransferase - metabolism; Sterol O-Acyltransferase - physiology; ATP binding cassette transporter A1; acyl-coenzyme A:cholesterol acyltransferase; apolipoprotein A-I; protein kinase C
• DOI: 10.1194/jlr.M400264-JLR200
• ISSN: 0022-2275

Differential regulation has been suggested for cellular cholesterol and phospholipid release mediated by apolipoprotein A-I (apoA-I)/ABCA1. We investigated various factors involved in cholesterol mobilization related to this pathway. ApoA-I induced a rapid decrease of the cellular cholesterol compartment that is in equilibrium with the ACAT-accessible pool in cells that generate cholesterol-rich HDL. Pharmacological and genetic inactivation of ACAT enhanced the apoA-I-mediated cholesterol release through upregulation of ABCA1 and through cholesterol enrichment in the HDL generated. Pharmacological activation of protein kinase C (PKC) also decreased the ACAT-accessible cholesterol pool, not only in the cells that produce cholesterol-rich HDL by apoA-I (i.e., human fibroblast WI-38 cells) but also in the cells that generate cholesterol-poor HDL (mouse fibroblast L929 cells). In L929 cells, the PKC activation caused an increase in apoA-I-mediated cholesterol release without detectable change in phospholipid release and in ABCA1 expression. These results indicate that apoA-I mobilizes intracellular cholesterol for the ABCA1-mediated release from the compartment that is under the control of ACAT. The cholesterol mobilization process is presumably related to PKC activation by apoA-I.