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

Katharina B Kuentzel1, Ivan Bradić1, Alena Akhmetshina1

  • 1Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.

International Journal of Molecular Sciences
|October 13, 2021
PubMed

Insights

Lysosomal acid lipase (LAL) deficiency impairs fetal development by disrupting cholesterol homeostasis, leading to severe lipid accumulation in infants. Early life is critical for LAL deficiency progression.

Area of Science:

  • Biochemistry
  • Developmental Biology
  • Genetics

Background:

  • Cholesterol and fatty acids are vital lipids for membrane synthesis and fetal development.
  • Cholesteryl esters (CE) are broken down by hormone-sensitive lipase (HSL) and lysosomal acid lipase (LAL).
  • LAL deficiency causes severe infantile pathologies, but its role in early development is unclear.

Purpose of the Study:

  • To investigate the effects of impaired CE degradation on fetal and infant development using mouse models.
  • To understand the consequences of defective lysosomal lipolysis during early life.

Main Methods:

  • Utilized Lal and Hsl knockout (-/-) mouse models.
  • Analyzed placental and fetal cholesterol homeostasis.
  • Examined hepatic lysosomal lipid accumulation in fetuses and postnatal mice.

Main Results:

  • Defective lysosomal lipolysis (LAL deficiency) disrupted placental and fetal cholesterol metabolism.
  • Lal-/- fetuses showed early signs of disease with hepatic lysosomal lipid accumulation in utero.
  • Postnatal LAL deficiency worsened, with massive hepatic lipid buildup continuing into adulthood.

Conclusions:

  • Lysosomal acid lipase (LAL) plays a critical role in early development and cholesterol homeostasis.
  • Defective LAL function leads to severe lipid storage disorders, particularly impacting fetal development and infant maturation.
  • The initial weeks after birth are crucial for the exacerbation of LAL deficiency symptoms.

Keywords:
cholesterol catabolismdevelopmentlysosomal acid lipaselysosomal storage disordermutant mouse modelsplacenta

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