Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria.
Int J Mol Sci. 2022 Oct 14;23(20):12286. doi: 10.3390/ijms232012286.
Advanced maternal age and obesity are the main risk factors to develop gestational diabetes mellitus (GDM). Obesity is a consequence of the increased storage of triacylglycerol (TG). Cytosolic and lysosomal lipid hydrolases break down TG and cholesteryl esters (CE) to release fatty acids (FA), free cholesterol, and glycerol. We have recently shown that intracellular lipases are present and active in the mouse placenta and that deficiency of lysosomal acid lipase alters placental and fetal lipid homeostasis. To date, intracellular lipid hydrolysis in GDM has been poorly studied despite the important role of FA in this condition. Therefore, we hypothesized that intracellular lipases are dysregulated in pregnancies complicated by maternal high-fat/high-cholesterol (HF/HCD) feeding with and without GDM. Placentae of HF/HCD-fed mice with and without GDM were more efficient, indicating increased nutrient transfer to the fetus. The increased activity of placental CE but not TG hydrolases in placentae of dams fed HF/HCD with or without GDM resulted in upregulated cholesterol export to the fetus and placental TG accumulation. Our results indicate that HF/HCD-induced dysregulation of placental lipid hydrolysis contributes to fetal hepatic lipid accumulation and possibly to fetal overgrowth, at least in mice.
高龄产妇和肥胖是妊娠糖尿病（GDM）的主要危险因素。肥胖是三酰甘油（TG）过度储存的结果。细胞质和溶酶体脂质水解酶将 TG 和胆固醇酯（CE）分解为释放脂肪酸（FA）、游离胆固醇和甘油。我们最近表明，细胞内脂肪酶存在于小鼠胎盘并具有活性，并且溶酶体酸性脂肪酶的缺乏会改变胎盘和胎儿的脂质稳态。尽管 FA 在这种情况下具有重要作用，但迄今为止，GDM 中的细胞内脂质水解仍未得到充分研究。因此，我们假设在伴有和不伴有 GDM 的高脂肪/高胆固醇（HF/HCD）喂养的妊娠中，细胞内脂肪酶失调。有和没有 GDM 的 HF/HCD 喂养的小鼠胎盘的效率更高，表明向胎儿的营养转移增加。胎盘 CE 而不是 TG 水解酶在有和没有 GDM 的 HF/HCD 喂养的母鼠胎盘中的活性增加导致胆固醇向胎儿的输出增加和胎盘 TG 积累。我们的研究结果表明，HF/HCD 诱导的胎盘脂质水解失调导致胎儿肝脏脂质积累，并且至少在小鼠中可能导致胎儿过度生长。
