Lysosomal acid lipase deficiency (LAL-D) begins affecting fetuses in utero and quickly exacerbates after birth, according to results published in the International Journal of Molecular Sciences. The study, performed in Lal knockout (Lal-/-) mice, showed that LAL-D alters lipid homeostasis in the placenta and unborn fetuses.

The altered lipid homeostasis resulted in cholesteryl esters (CE) accumulation and CE crystal formation in the placenta and fetal tissues, including the liver and small intestine, which indicated early manifestations of LAL-D. Although elevated levels of CE were observed, no fetal growth differences were observed between Lal-/- and wild-type (WT) mice on day 19 of pregnancy. 

The study did find that even 2 days after birth, Lal-/- mice were already slightly smaller (P =.0743) than WT and had visibly paler and more yellowish livers, indicating massive accumulation of CE and triglycerides (TG).

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By 2 and 4 weeks postpartum, Lal-/- pups were significantly smaller than WT pups and had roughly 50% less subcutaneous white adipose tissue and increased liver weights. At 4 weeks of age, the Lal-/- pups had a 25-fold increase in CE liver concentrations. This was a shift from week 2 results that showed a 3.1-fold CE accumulation and a 3.6-fold TG accumulation.

“Taken together, our data demonstrate that LAL deficiency exhibits its major phenotypic features already in utero. With dietary fat intake through the maternal milk as the main source of energy, the disease progresses rapidly in Lal-/- pups, with full manifestation of LAL deficiency as early as 4 weeks after birth,” the authors said.

The study also investigated the effect of hormone-sensitive lipase (HSL) deficiency on mice. HSL knockout (Hsl-/-) mice did not show significant changes in placental or fetal growth compared to WT. There was also no change in organ development in utero. However, downregulation of mRNA related to genes that regulate cholesterol synthesis was observed.

Lal-/- mice were bred through the crossing of heterozygous (Lal+/-) parents and were then genotyped. Hsl-/- animals were bred from Hsl-/- females with Hsl+/- males since homozygous males are sterile.


Kuentzel KB, Bradić I, Akhmetshina A, et al. Defective lysosomal lipolysis causes prenatal lipid accumulation and exacerbates immediately after birth. Int J Mol Sci. 2021;22(19):10416. doi:10.3390/ijms221910416