Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humans
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Authors
Helderman, Ron C.Whitney, Daniel G.
Duta-Mare, Madalina
Akhmetshina, Alena
Vujic, Nemanja
Jayapalan, Shobana
Nyman, Jeffry S.
Misra, Biswapriya B.
Rosen, Clifford J.
Czech, Michael P.
Kratky, Dagmar
Rendina-Ruedy, Elizabeth
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2021-07-01Keywords
BoneCholesterol
Lipid
Lipophagy
Metabolism
Osteoblast
Skeleton
Biochemical Phenomena, Metabolism, and Nutrition
Cell and Developmental Biology
Cellular and Molecular Physiology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Enzymes and Coenzymes
Lipids
Musculoskeletal Diseases
Musculoskeletal System
Nutritional and Metabolic Diseases
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Lysosomal acid lipase (LAL) is essential for cholesteryl ester (CE) and triacylglycerol (TAG) hydrolysis in the lysosome. Clinically, an autosomal recessive LIPA mutation causes LAL deficiency (LALD), previously described as Wolman Disease or Cholesteryl Ester Storage Disease (CESD). LAL-D is associated with ectopic 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 for bone formation, and ultimately, skeletal health. To investigate the role of LAL in skeletal homeostasis, we used LAL-deficient ((-/-)) mice, in vitro osteoblast cultures, and novel clinical data from LAL-D patients. Both male and female LAL(-/-) mice demonstarted lower trabecular and cortical bone parameters , which translated to reduced biomechanical properties. Further histological analyses revealed that LAL(-/-) mice had fewer osteoblasts, with no change in osteoclast or marrow adipocyte numbers. In studying the cell-autonomous role of LAL, we observed impaired differentiation 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(R)) which revealed that adults ( > /=18 years) with CESD (n = 3076) 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.Source
Helderman RC, Whitney DG, Duta-Mare M, Akhmetshina A, Vujic N, Jayapalan S, Nyman JS, Misra BB, Rosen CJ, Czech MP, Kratky D, Rendina-Ruedy E. Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humans. Bone. 2021 Jul;148:115946. doi: 10.1016/j.bone.2021.115946. Epub 2021 Apr 7. PMID: 33838322; PMCID: PMC8108562. Link to article on publisher's site
DOI
10.1016/j.bone.2021.115946Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41867PubMed ID
33838322Related Resources
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© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.bone.2021.115946
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Except where otherwise noted, this item's license is described as © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).