New therapeutic targets for atherosclerotic plaques - The role of acyl CoA : cholesterol acyltransferase and neutral cholesterol ester hydrolase in foam cell formation

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Cholesterol-ester (CE)-laden foam cells are a hallmark of atherosclerosis. Cholesterol is in a dynamic equilibrium between free and esterified form. The esterification and hydrolysis are mediated by acyl CoA : cholesterol acyltransferase (ACAT) and neutral cholesterol ester hydrolase (NCEH), respectively. In the current study, we investigated the role of ACAT-1, an ACAT isoform, and hormone-sensitive lipase (HSL) responsible for NCEH in foam cell formation and atherogenesis.We have generated ACAT-1 null (ACAT-1-/-) mice, which had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities. To determine the role of ACAT-1 in atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein (apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous xanthomatosis with loss of hair in both ACAT-1/-:apoE-/- and ACAT-1-/-:LDLR-/- mice. Free cholesterol content was significantly increased in their skin. Aortic fatty streak lesion size as well as cholesterol ester content were moderately reduced in both mutant mice compared with their respective controls. These results indicate that the local inhibition of ACAT activity in tissue macrophages is protective against cholesteryl ester accumulation but causes cutaneous xanthomatosis in mice lacking apo E or LDLR. Furthermore, we generated HSL-null (HSL-/-) mice, whose macrophages had a substantial activity of NCEH compared with those of wild-type. Consistently, lack of HSL did not aggravate the accumulation of CE in macrophages. Thus, it is rational that HSL is not the primary enzyme for NCEH in macrophages. However, adenoviral mediated overexpression of HSL markedly reduced the CE accumulation through accelerated hydrolysis of CE and decreased uptake of modified lipoproteins.