2 Maternal-Fetal Transfer of Vitamin A …
39
Overall, RBP
−/− dams deprived of dietary VA mimic the status of VA-deficient pregnant women, providing a unique experimental model to analyze the metabolic links
between maternal nutrition and developmental abnormalities.
Kim and colleagues (2011) demonstrated the importance of the maternal hepatic
retinoid stores for supporting normal embryogenesis when dietary VA is limiting.
These authors generated mice lacking both RBP and lecithin: retinol acyltransferase
(LRAT), the enzyme that primarily contributes to the hepatic formation of retinyl
esters (the storage form of VA) by esterifying retinol (O’Byrne and Blaner 2013).
Dietary VA deprivation of LRAT
−/− RBP
−/− females during pregnancy resulted in a
severe retinoid-deficient embryonic phenotype, even in the case of LRAT
+/− RBP
−/−
embryos, indicating that the severe retinoid-deficient status of the double-mutant
dams, rather than the lack of LRAT in the embryos, caused the developmental defects
(Kim et al. 2008).
Interestingly, under normal circumstances (normal maternal VA status and presence of a functional RBP—i.e., sufficient hepatic retinoid stores), the retinol-RBP
pathway is the primary contributor to fetal development, while the retinyl ester pathway is largely responsible for the accumulation of fetal retinoid stores (Quadro et al.
2004a, b). Nevertheless, dietary VA can sufficiently sustain proper embryogenesis
if maternal liver stores are depleted or cannot be properly mobilized (Quadro et al.
2004a, b, 2005).
Mechanisms of Maternal-Fetal Transfer of VA-Containing
Lipoprotein
Further studies by Wassef and Quadro (Wassef and Quadro 2011) investigated the
mechanisms whereby retinyl esters within chylomicrons and/or chylomicron remnants are taken across the maternal-fetal barrier and transferred to the embryo, with
a specific focus on the function of lipoprotein lipase (LPL). LPL is a major enzyme
of lipid metabolism responsible for the hydrolysis of the core triglycerides in chylomicrons and very low-density lipoprotein, and the subsequent release of free fatty
acids (Merkel et al. 2002). The chylomicron remnants generated by this hydrolysis
can be taken up by a receptor-mediated mechanism or by the “bridging function”
of LPL (which draws the remnants near to lipoprotein receptors such as LRP1 and
LDLR) (Bharadwaj et al. 2010). In these studies, the authors used LPL knockout
mice overexpressing human LPL under the muscle-creatine kinase promoter (ML0)
(Levak-Frank et al. 1995) and also introduced this transgene on the RBP
− /
− background (ML0RBP
−/− ) (Wassef and Quadro 2011). The ML0 and ML0RBP
−/− strains
do not express mouse or human LPL in the placenta and thus are suitable models to
specifically address the role of placental LPL in mediating the transfer of retinoids
across this tissue. By tracing radioactive VA given to these mice in a bolus dose in the
presence or absence of a lipase inhibitor, Wassef and Quadro (Wassef and Quadro
2011) showed that (see Fig. 2.3):
39
Overall, RBP
−/− dams deprived of dietary VA mimic the status of VA-deficient pregnant women, providing a unique experimental model to analyze the metabolic links
between maternal nutrition and developmental abnormalities.
Kim and colleagues (2011) demonstrated the importance of the maternal hepatic
retinoid stores for supporting normal embryogenesis when dietary VA is limiting.
These authors generated mice lacking both RBP and lecithin: retinol acyltransferase
(LRAT), the enzyme that primarily contributes to the hepatic formation of retinyl
esters (the storage form of VA) by esterifying retinol (O’Byrne and Blaner 2013).
Dietary VA deprivation of LRAT
−/− RBP
−/− females during pregnancy resulted in a
severe retinoid-deficient embryonic phenotype, even in the case of LRAT
+/− RBP
−/−
embryos, indicating that the severe retinoid-deficient status of the double-mutant
dams, rather than the lack of LRAT in the embryos, caused the developmental defects
(Kim et al. 2008).
Interestingly, under normal circumstances (normal maternal VA status and presence of a functional RBP—i.e., sufficient hepatic retinoid stores), the retinol-RBP
pathway is the primary contributor to fetal development, while the retinyl ester pathway is largely responsible for the accumulation of fetal retinoid stores (Quadro et al.
2004a, b). Nevertheless, dietary VA can sufficiently sustain proper embryogenesis
if maternal liver stores are depleted or cannot be properly mobilized (Quadro et al.
2004a, b, 2005).
Mechanisms of Maternal-Fetal Transfer of VA-Containing
Lipoprotein
Further studies by Wassef and Quadro (Wassef and Quadro 2011) investigated the
mechanisms whereby retinyl esters within chylomicrons and/or chylomicron remnants are taken across the maternal-fetal barrier and transferred to the embryo, with
a specific focus on the function of lipoprotein lipase (LPL). LPL is a major enzyme
of lipid metabolism responsible for the hydrolysis of the core triglycerides in chylomicrons and very low-density lipoprotein, and the subsequent release of free fatty
acids (Merkel et al. 2002). The chylomicron remnants generated by this hydrolysis
can be taken up by a receptor-mediated mechanism or by the “bridging function”
of LPL (which draws the remnants near to lipoprotein receptors such as LRP1 and
LDLR) (Bharadwaj et al. 2010). In these studies, the authors used LPL knockout
mice overexpressing human LPL under the muscle-creatine kinase promoter (ML0)
(Levak-Frank et al. 1995) and also introduced this transgene on the RBP
− /
− background (ML0RBP
−/− ) (Wassef and Quadro 2011). The ML0 and ML0RBP
−/− strains
do not express mouse or human LPL in the placenta and thus are suitable models to
specifically address the role of placental LPL in mediating the transfer of retinoids
across this tissue. By tracing radioactive VA given to these mice in a bolus dose in the
presence or absence of a lipase inhibitor, Wassef and Quadro (Wassef and Quadro
2011) showed that (see Fig. 2.3):