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

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 (-/-) 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.

Dysregulation of Placental Lipid Hydrolysis by High-Fat/High-Cholesterol Feeding and Gestational Diabetes Mellitus in Mice

“…Biochemical quantification of lipids showed a tendency toward elevated TG levels in HF/HCD without GDM and significantly increased TG concentrations (2.1-fold) in placentae of GDM dams, whereas total cholesterol (TC) and CE concentrations were not affected ( Figure 2 B). In line with results from our previous study [ 17 ], the most abundant lipid in the placenta was cholesterol, more specifically FC ( Figure 2 B). Increased placental lipid levels prompted us to further examine the occurrence and activities of intracellular lipases.…”

“…Unexpectedly, we observed increased neutral and acid CE hydrolysis, in line with transcriptional upregulation of the respective lipid hydrolases, suggesting increased CE turnover in HF/HCD and GDM placentae. The enzymes responsible for placental CE hydrolysis are LAL at acidic pH and HSL at neutral pH, the only known CE-degrading lipases expressed and active in the mouse placenta [ 17 ]. Increased acid TG lipase activity observed in the present study confirms previous data from streptozotocin-injected rats and diabetic humans [ 38 ].…”

“…Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL) catalyze the release of FA from cytosolic TG, DG, MG, and CE [ 12 , 13 , 14 ], whereas lysosomal acid lipase (LAL) is the sole enzyme known to hydrolyze these lipids in the lysosomal lumen [ 15 ], from where FA and free cholesterol (FC) are further exported into the cytosol [ 16 ]. We have recently shown that the intracellular CE hydrolases LAL and HSL are expressed and active in the mouse placenta and that LAL deficiency leads to the disturbance of placental lipid metabolism [ 17 ]. Transcriptomics and metabolomics analyses revealed altered lipid metabolism in placental cells under high glucose conditions [ 18 ] and that placental lipids are the main metabolites with variable abundance in women with GDM [ 19 ].…”

Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases

“…Neutral (pH 7) and acid (pH 4.5) CEH and TGH activities were measured in cell and tissue lysates by using radioactively labeled substrates as described previously [ 42 ] with minor modifications. Briefly, tissues and cells were lysed in neutral lysis buffer (100 mM potassium phosphate, 1 mM dithiothreitol (Carl Roth, Karlsruhe, Germany), pH 7), sonicated twice on ice for 10 s, and centrifuged at 1,000× g and 4 °C for 10 min.…”

Serine Hydrolases in Lipid Homeostasis of the Placenta-Targets for Placental Function?

“…Recently, a study investigated the effect of genetic disruption of murine LAL and demonstrated CE accumulation in placentae and fetuses, suggesting that lysosomal rather than neutral lipolysis already alters placental and fetal cholesterol homeostasis in utero . Furthermore, LAL deficiency led to massive hepatic lysosomal lipid accumulation after birth, with a severe progression in young adulthood [ 71 ]. The insight that aberrant LAL expression leads to a severe metabolic disorder not only during pregnancy but also in the first weeks of life in mice underlines the crucial role of this hydrolase in lysosomal CE metabolism.…”