Lysosomal acid lipase (LAL) is essential for cholesteryl ester (CE) and triacylglycerol (TAG) hydrolysis in lysosomes. Clinically, an autosomal recessive LIPA mutation causes LAL deficiency (LAL-D), either Wolman Disease or Cholesterol Ester Storage Disease (CESD). LAL-D is associated with ectopic neutral lipid accumulation in the liver, small intestine, spleen, adrenal glands, and blood. Considering the importance of unesterified cholesterol and fatty acids in bone metabolism, we hypothesized that LAL is essential to bone formation, and ultimately, skeletal health. To investigate the role of LAL in skeletal homeostasis, we used LAL-deficient () mice and osteoblast cell cultures. Male LAL mice had lower trabecular BV/TV (12%) compared to WT mice (21%), due to decreased trabecular number and increased trabecular separation; this change was not apparent in the females. While both sexes of LAL mice displayed decreased cortical bone thickness and polar moment of inertia, only the female LAL mice showed increased cortical porosity. Histological analyses revealed that LAL mice tended to have less osteoblasts but no change in osteoclast numbers. In studying the cell-autonomous role of LAL, we observed impaired osteoblastogenesis of LAL calvarial osteoblasts and in bone marrow stromal cells treated with the LAL inhibitor lalistat. Consistent with LAL’s role in other tissues, lalistat resulted in profound lipid puncta accumulation and an altered intracellular lipid profile. Finally, we analyzed a large de-identified national insurance database (i.e. 2016/2017 Optum Clinformatics®) which revealed that adults (≥18 years) with CESD (n=3,076) had a higher odds ratio (OR=1.21; 95% CI=1.03-1.41) of all-cause fracture at any location compared to adults without CESD (n=13.7 M) after adjusting for demographic variables and osteoporosis. These data demonstrate that alterations in LAL have significant clinical implications related to fracture risk and that LAL’s modulation of lipid metabolism is a critical for osteoblast function.
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