Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kuentzel, K.
Role of intracellular lipid hydrolases in lipid and energy metabolism in murine placenta and fetus
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gauster Martin
- Kratky Dagmar
- Wadsack Christian
- Altmetrics:
- Abstract:
- Cholesterol and fatty acids (FA) are essential lipids and highly important for membrane biosynthesis and fetal organ development. To date, two enzymes are known to hydrolyze cholesteryl esters (CE) in different cellular compartments. Hormone-sensitive lipase (HSL) acts as neutral CE hydrolase and releases free cholesterol and FA from cytosolic lipid droplets. Lysosomal acid lipase (LAL) breaks down CE in the lysosome at an acidic pH. Nonfunctional LAL or HSL leads to human pathologies manifested by defective whole-body lipid homeostasis. The role of CE hydrolases in the placenta and fetal development is currently poorly understood. Therefore, this project aimed to investigate how defective cholesterol catabolism affects the mouse placenta and the developing fetus. Loss of HSL (Hsl-/-) had no impact on placental/fetal weight and on placental or fetal liver lipid content at the end of pregnancy, arguing for a minor role of HSL in placental lipid metabolism. Unaltered lipid levels in Hsl-/- placentae occurred mainly due to a compensatory downregulation of cholesterol synthesis. In contrast, Lal-deficient (Lal-/-) placentae accumulated CE and CE crystals. Already on day 19 of pregnancy, Lal-/- fetuses accumulated CE in the liver and intestine, whereas TG concentrations remained unchanged. Electron microscopy and immunofluorescence imaging revealed the abundance of hepatic CE crystals and fatty lysosomes in unborn Lal-/- offspring. Two weeks after birth, Lal-deficient pubs already show the adult Lal-/- phenotype with increased liver weight and both CE and triglyceride (TG) accumulation, which aggravated until week 4. Impaired acid but not neutral CE hydrolysis affected cholesterol homeostasis in the placenta. Our data highlighted the crucial role of LAL during fetal development since the unborn offspring was already affected by hepatic lipid accumulation at the end of pregnancy. In addition to intrauterine development, the first weeks after birth appeared to be important for the manifestation of the disease. To date, intracellular lipid hydrolysis in gestational diabetes mellitus (GDM) has been poorly studied, although FA play an important role in this condition. Therefore, we hypothesized that intracellular lipases are dysregulated in pregnancies complicated by GDM. Placentae of pregnant mice fed a high-fat/high-cholesterol diet (HF/HCD) or of mice with GDM were smaller than those of chow diet-fed controls, despite heavier fetuses. Fetal overgrowth and decreased placental weight indicated higher placental efficiency. Gene expression levels of cytosolic (Atgl, Hsl, Mgl) and acid (Lipa) lipases were significantly upregulated in placentae upon maternal HF/HCD and GDM. GDM mice displayed increased placental TG content as a result of decreased neutral TG hydrolase activity, whereas CE levels remained unchanged on gestational day 19. Elevated fetal hepatic CE and TG concentrations indicated an increased cholesterol and FA transport through the placenta to the fetus. These results so far indicate that in pregnancies complicated by obesity or GDM, lipid hydrolases are differentially expressed and active compared with healthy controls, suggesting that dysregulated placental lipolysis contributes to fetal hepatic lipid accumulation, at least in mice.