Sterol O-acyltransferase 2 (SOAT2), also known as ACAT2, is the major cholesterol esterifying enzyme in the liver and small intestine (SI). Esterified cholesterol (EC) carried in certain classes of plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease (WD) or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to what effect the loss of SOAT2 function might have on tissue EC sequestration in LAL-deficient mice. When weaned at 21 days, Lal(-/-):Soat2(+/+) mice had a whole liver cholesterol content (mg/organ) of 24.7 mg vs 1.9 mg in Lal(+/+):Soat2(+/+) littermates, with almost all the excess sterol being esterified. Over the next 31 days, liver cholesterol content in the Lal(-/-):Soat2(+/+) mice increased to 145 +/- 2 mg but to only 29 +/- 2 mg in their Lal(-/-):Soat2(-/-) littermates. The level of EC accumulation in the SI of the Lal(-/-):Soat2(-/-) mice was also much less than in their Lal(-/-):Soat2(+/+) littermates. In addition, there was a >70% reduction in plasma transaminase activities in the Lal(-/-):Soat2(-/-) mice. These studies illustrate how the severity of disease in a mouse model for CESD can be substantially ameliorated by elimination of SOAT2 function. (C) 2014 Elsevier Inc. All rights reserved.