Although only a small proportion of cholesterol in the body is esterified, in 
several diseases marked expansion of the esterified cholesterol (EC) pool 
occurs. These include Wolman disease (WD) and Cholesteryl Ester Storage Disease 
(CESD) which both result from mutations in LIPA, the gene that encodes lysosomal 
acid lipase (LAL). The respective contributions that our three cholesterol 
esterifying enzymes make to EC production, especially in disorders like CESD, 
are not well defined. The current studies represent a detailed exploration of 
our earlier findings in young male LAL-deficient mice also missing sterol 
O-acyltransferase 2 (SOAT2, also called ACAT2). Here we show that, even as they 
aged, male and female Lal-/-: Soat2- /- mice, compared to Lal-/-: Soat2+/+ 
littermates, had appreciably less hepatomegaly as well as a marked reduction in 
the level of sequestration of EC, in liver transaminase activities, and in 
hepatic mRNA expression levels for markers of inflammation. Loss of SOAT2 
function also dramatically curtailed EC entrapment in the small intestine of the 
LAL-deficient mice. Together, these data imply that SOAT2 inhibition, if applied 
concurrently with enzyme replacement therapy for LAL deficiency, may blunt the 
re-esterification of newly released unesterified cholesterol thereby improving 
clinical outcomes.