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Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth

Kuentzel, Katharina B LU orcid ; Bradić, Ivan ; Akhmetshina, Alena ; Korbelius, Melanie ; Rainer, Silvia ; Kolb, Dagmar ; Gauster, Martin ; Vujić, Nemanja and Kratky, Dagmar (2021) In International Journal of Molecular Sciences 22(19).
Abstract

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-)... (More)

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.

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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Animals, Newborn, Disease Models, Animal, Humans, Lipolysis, Liver/metabolism, Lysosomes/metabolism, Mice, Mice, Knockout, Sterol Esterase/deficiency, Wolman Disease/genetics
in
International Journal of Molecular Sciences
volume
22
issue
19
article number
10416
publisher
MDPI AG
external identifiers
  • scopus:85115791415
  • pmid:34638755
ISSN
1422-0067
DOI
10.3390/ijms221910416
language
English
LU publication?
no
id
14733483-64d1-48c0-87fe-2709fd26dae7
date added to LUP
2022-10-10 16:25:56
date last changed
2024-06-27 15:50:52
@article{14733483-64d1-48c0-87fe-2709fd26dae7,
  abstract     = {{<p>Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.</p>}},
  author       = {{Kuentzel, Katharina B and Bradić, Ivan and Akhmetshina, Alena and Korbelius, Melanie and Rainer, Silvia and Kolb, Dagmar and Gauster, Martin and Vujić, Nemanja and Kratky, Dagmar}},
  issn         = {{1422-0067}},
  keywords     = {{Animals; Animals, Newborn; Disease Models, Animal; Humans; Lipolysis; Liver/metabolism; Lysosomes/metabolism; Mice; Mice, Knockout; Sterol Esterase/deficiency; Wolman Disease/genetics}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{19}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth}},
  url          = {{http://dx.doi.org/10.3390/ijms221910416}},
  doi          = {{10.3390/ijms221910416}},
  volume       = {{22}},
  year         = {{2021}},
}