Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice

Abstract

Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of cholesterol, and whole body cholesterol pool size in a mouse model of CESD. In 50-day-old lal(-/-) and matching lal(+/+) mice fed a low-cholesterol diet, whole animal cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal(-/-) mice sequestered cholesterol at an average rate of 3.2 mg·day(-1)·animal(-1). The proportion of the body sterol pool contained in the liver of the lal(-/-) mice was 64 vs. 6.3% in their lal(+/+) controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal(-/-) mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal(-/-) mice, whole liver cholesterol synthesis increased 10.2-fold, resulting in a 3.2-fold greater rate of whole animal sterol synthesis compared with their lal(+/+) controls. The rate of cholesterol synthesis in the lal(-/-) mice exceeded that in the lal(+/+) controls by 3.7 mg·day(-1)·animal(-1). Fractional cholesterol absorption and fecal bile acid excretion were unchanged in the lal(-/-) mice, but their rate of neutral sterol excretion was 59% higher than in their lal(+/+) controls. Thus, in this model, the continual expansion of the body sterol pool is driven by the synthesis of excess cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal(-/-) mice was 355 days.

PRD125, a Potent and Selective Inhibitor of SterolO-Acyltransferase 2 Markedly Reduces Hepatic Cholesteryl Ester Accumulation and Improves Liver Function in Lysosomal Acid Lipase-Deficient Mice

“…4A). A documented feature of LAL-deficient mice is an increased rate of fecal neutral sterol excretion (Aqul et al, 2014). This was evident from a comparison of the data for the chow-fed mutants versus wild-types in the current studies (Fig.…”

“…In mice, the lifespan of the absorptive cells is only 2-3 days (Lipkin, 1981). If this turnover did not occur, the intestinal EC levels found in Lal 2/2 mice would likely be even more elevated than shown here and in previous publications (Du et al, 2001;Aqul et al, 2014). Nevertheless, based on the present findings, the EC levels in either Lal 2/2 :Soat2 2/2 mice or PRD125-treated LAL mutants would still be expected to be much lower than in unmanipulated Lal 2/2 mice of the same age.…”

“…Although hepatomegaly is pronounced in Lal 2/2 mice by early adulthood, the mass of their small intestine has not changed significantly at that time. However, there are already marked histologic changes and increased levels of EC, both of which become very pronounced as disease progresses (Du et al, 2001;Aqul et al, 2014). The fall in intestinal EC concentration in the LAL mutants given PRD125 (Fig.…”

“…Lal 2/2 Mice Given PRD125 Showed Substantial Reductions in Liver Inflammation and Plasma Transaminase Activities. One of the most striking features of livers from Lal 2/2 mice, apart from their size and EC content, is their pronounced degree of inflammation and macrophage infiltration (Du et al, 2001;Aqul et al, 2014). The data in Fig.…”

“…Subsequently, a mouse model for CESD was developed (Du et al, 2001). A detailed characterization of multiple parameters of cholesterol metabolism in a CESD mouse model was recently reported (Aqul et al, 2014).…”