Uptake of Dietary Retinoids at the Maternal-Fetal Barrier

Abstract

Dietary retinoids (vitamin A and its derivatives) contribute to normal embryonic development. However, the mechanism(s) involved in the transfer of recently ingested vitamin A from mother to embryo is not fully understood. We investigated in vivo whether lipoprotein lipase (LPL) facilitates the placental uptake of dietary retinyl ester incorporated in chylomicrons and their remnants and its transfer to the embryo. We examined the effects of both genetic ablation (MCK-L0 mice) and pharmacological inhibition (P-407) of LPL by maintaining wild type and MCK-L0 mice on diets with different vitamin A content or administering them an oral gavage dose of [ 3 H]retinol with or without P-407 treatment. We showed that LPL expressed in placenta facilitates uptake of retinoids by this organ and their transfer to the embryo, mainly through its catalytic activity. In addition, through its "bridging function," LPL can mediate the Vitamin A, a fat-soluble vitamin, is an essential nutrient obtained from food. Regardless of its dietary origin (retinol, retinyl ester, provitamin A carotenoids), the ingested vitamin A is packaged within the enterocytes as retinyl esters into chylomicrons, which are lipoprotein particles containing triglycerides, fat soluble vitamins, cholesterol, and proteins. Once secreted into the lymphatic system, the chylomicron particle reaches the general circulation, where its triglyceride core is hydrolyzed by the enzyme lipoprotein lipase (LPL) 2 on the surface of capillary endothelial cells in extrahepatic tissues such as adipose and muscle (1, 2). This hydrolysis leads to the formation of smaller particles called chylomicron remnants, which still contain retinyl esters (3). A large portion of the retinyl ester-containing chylomicron remnants are rapidly cleared by the liver, the major site of vitamin A storage in the body. However, ϳ25% of them are taken up by extrahepatic tissues (4, 5), including embryonic and extra-embryonic tissues (6). Retinoids (vitamin A and its derivatives) are vital for reproduction and embryogenesis (7-9). The mammalian embryo relies on retinoids circulating in the maternal bloodstream for its supply of vitamin A. Within the maternal circulation, retinol bound to its sole specific carrier retinol-binding protein (RBP, also known as RBP4) is the most abundant retinoid form in the fasting state (10, 11). In the fed state, retinyl esters packaged in chylomicrons and their remnants may account for the majority of circulating retinoids. Fetal development can exclusively rely on postprandial retinoids, at least up to a certain extent, if the retinol-RBP pathway is impaired (6, 12). Hence, retinyl esters within chylomicrons and/or chylomicron remnants must be taken up by the maternal-fetal barrier, i.e. placenta and yolk sac, and transferred to the embryo. However, the exact mechanisms that mediate this process are poorly understood. LPL is a major enzyme in lipid metabolism responsible for the hydrolysis of the core triglycerides in chylomicrons and very low density lipoprotein and su...

Diet-dependent retinoid effects on liver gene expression include stellate and inflammation markers and parallel effects of the nuclear repressor Shp

“…These genes exhibit closely correlated expression in individual mice across multiple treatments. RBP1 and LPL function together to mediate the uptake of lipids and RE through LRP-1-mediated processing of chylomicron remnants [44]. This HF cluster includes several lipid metabolism genes, which may participate in this process, such as nuclear receptors Nr1i3/Car and Nr4a1 [2, 45].…”

Retinol and Betacarotene Status in Mother-Infant Dyads and Associations between Them

“…Evidence suggests that maternal retinol levels exert a downregulation in the input mechanisms of pro-vitamin A carotenoids through the fetal-placental barrier mediated by low density lipoprotein receptor-related protein 1 and lipoprotein lipase [41, 42], as well as acting in the same way on the activity of placental BCMOI [43]. …”

Tissue- and sex-specific effects of β-carotene 15,15′ oxygenase (BCO1) on retinoid and lipid metabolism in adult and developing mice

“…A detailed method has been described previously [14, 27]. Briefly, RNA concentrations were measured followed by DNase I treatment (Roche Diagnostics, IN).…”