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

International Journal of Molecular Sciences

Dagmar Kolb¹  Martin Gauster¹  Dagmar Kratky²  Katharina B. Kuentzel²  Alena Akhmetshina²  Silvia Rainer²  Nemanja Vujić²  Melanie Korbelius²  Ivan Bradić² 

[1] Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Austria;Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria;

关键词: cholesterol catabolism;    lysosomal acid lipase;    lysosomal storage disorder;    placenta;    development;    mutant mouse models;   

DOI  :  10.3390/ijms221910416

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown