Increased expression of acyl-coenzyme A: cholesterol acyltransferase-1 and elevated cholesteryl esters in the hippocampus after excitotoxic injury

Abstract: Significant increases in levels of cholesterol and cholesterol oxidation products are detected in the hippocampus undergoing degeneration after excitotoxicity induced by the potent glutamate analog, kainate (KA), but until now, it is unclear whether the cholesterol is in the free or esterified form. The present study was carried out to examine the expression of the enzyme involved in cholesteryl ester biosynthesis, acyl-coenzyme A: cholesterol acyltransferase (ACAT) and cholesteryl esters after KA excitotoxicity. A 1000-fold greater basal mRNA level of ACAT1 than ACAT2 was detected in the normal brain. ACAT1 mRNA and protein were upregulated in the hippocampus at 1 and 2 weeks after KA injections, at a time of glial reaction. Immunohistochemistry showed ACAT1 labeling of oligodendrocytes in the white matter and axon terminals in hippocampal CA fields of normal rats, and loss of staining in neurons but increased immunoreactivity of oligodendrocytes, in areas affected by KA. Gas chromatography-mass spectrometry analyses confirmed previous observations of a marked increase in level of total cholesterol and cholesterol oxidation products, whilst nuclear magnetic resonance spectroscopy showed significant increases in cholesteryl ester species in the degenerating hippocampus. Upregulation of ACAT1 expression was detected in OLN93 oligodendrocytes after KA treatment, and increased expression was prevented by an antioxidant or free radical scavenger in vitro. This suggests that ACAT1 expression may be induced by oxidative stress. Together, our results show elevated ACAT1 expression and increased cholesteryl esters after KA excitotoxicity. Further studies are necessary to determine a possible role of ACAT1 in acute and chronic neurodegenerative diseases. [Copyright &y& Elsevier]