Acyl CoA binding protein and cholesterol differentially alter fatty acyl CoA utilization by microsomal acyl-CoA:cholesterol transferase

Hsu Chao, Minglong Zhou, Friedhelm Schroeder, and Ann B. Kier

Department of Pathobiology, Texas A&M University, College Station, TX 77843-4467

Corresponding Author: Akier{at}cvm.tamu.edu

Microsomal acyl CoA:cholesterol acyltransferase [ACAT] is stimulated by intracellular [sterol carrier protein-2 (SCP-2); liver fatty acid binding protein (L-FABP)] and extracellular [albumin] lipid binding proteins both in vitro and/or in intact cells. Since these proteins bind and transfer both substrates of the ACAT reaction, i.e. cholesterol and fatty acyl CoA, it is unclear whether enhancement of ACAT is due to interaction of these proteins with cholesterol and/or fatty acyl CoA. To establish the role of fatty acyl CoA binding, independent of cholesterol binding/transfer, the effect of acyl CoA binding protein (ACBP), which exclusively binds fatty acyl CoAs, on rat liver microsomal ACAT was compared to that of SCP-2, L-FABP, and BSA. ACBP was chosen because amino acid sequence analysis revealed that ACBP contains an endoplasmic reticulum(ER) retention motif. Further, double immunolabeling and confocal microscopy significantly colocalized ACBP with ACAT 2 and an ER marker in L-cell fibroblasts and hepatoma cells, respectively. It was shown for the first time that, in the presence of exogenous cholesterol, ACBP significantly stimulated ACAT. The ability of intracellular fatty acyl CoA binding proteins to stimulate microsomal ACAT in the presence of exogenous cholesterol was in the order of their relative affinities for fatty acyl CoA [ACBP > SCP-2 > L-FABP], but there was no correlation between their ability to transfer cholesterol. In contrast, in the absence of exogenous cholesterol all three intracellular fatty acyl CoA binding proteins inhibited microsomal ACAT in the order: ACBP > SCP-2 > L-FABP. The extracellular fatty acyl CoA/cholesterol binding protein BSA did not differentially modulate microsomal ACAT in the presence or absence of exogenous cholesterol, but instead always stimulated microsomal ACAT. Thus, ACBP was the most potent intracellular fatty acyl CoA binding protein in differentially modulating the activity of microsomal ACAT to form cholesteryl esters, independent of cholesterol binding/transfer ability.

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