Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA : cholesterol acyltransferase 1

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted co nsiderable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACA Ts. One of these enzymes, ACAT1, is highly expressed in macrophages in athe rosclerotic lesions, where it contributes to foam-cell formation. In this s tudy, we examined the effects of selective ACAT1 deficiency in two mouse mo dels of atherosclerosis. In the setting of severe hypercholesterolemia caus ed by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposit ion of unesterified cholesterol in the skin and brain. Bone marrow transpla ntation experiments demonstrated that ACAT1 deficiency in macrophages was s ufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relativel y lower serum cholesterol levels. However, the lesions in ACAT1-deficient m ice were atypical in composition, with reduced amounts of neutral lipids an d a paucity of macrophages in advanced lesions. Although the latter finding s may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in t he setting of severe hyperlipidemia may have detrimental consequences.