2 Maternal-Fetal Transfer of Vitamin A …
43
form and reach the developing embryo to serve as a source of VA for in situ synthesis of retinoids by the action of BCO1. Specifically, β-carotene supplementation of
BCO1
−/− RBP
−/− dams bred on the VA-deficient diet improved the retinoid levels
and congenital malformations of their BCO1
+/− RBP
−/− embryos (Kim et al. 2011).
Kim and colleagues also demonstrated that, aside from cleaving β-carotene to generate retinoids, embryonic BCO1 performs additional functions in retinoid and lipid
metabolism by modulating the esterification of retinol, cholesterol and diacylglycerols (Kim et al. 2015; Dixon et al. 2014). Although it has not been elucidated whether
this is a carotenoid-independent action of BCO1, this work confirmed the existence
of cross-talk between carotenoid and lipid metabolism (Kim et al. 2011; Palczewski
et al. 2016; Lee et al. 2014). This metabolic interaction could be particularly important during embryogenesis, given the critical role of lipids in proper development,
especially of the central nervous system (Haas and Muenke 2010; Farese et al. 1995,
1996). Other reports, some of which will be discussed below, further highlighted this
micro-macronutrient interaction and clearly indicated a novel avenue of research to
pursue in the future.
Regarding the transfer of β-carotene from the maternal to the fetal circulation
across the placenta, Quadro and colleagues hypothesized that this process depended
on lipoprotein metabolism, because β-carotene is transported in the adult bloodstream by lipoproteins [reviewed in (Parker 1996; Harrison 2012; Erdman et al.
1993)]. Moreover, the placenta acquires, assembles and secretes lipoproteins both
in vivo and in vitro (Kamper et al. 2015; Madsen et al. 2004). Serum β-carotene is
incorporated into chylomicrons, chylomicron remnants, VLDL, LDL, and even HDL
particles [reviewed in (Parker 1996; Harrison 2012; Erdman et al. 1993)]. Therefore,
its tissue uptake was hypothesized to be mediated by the same key regulators involved
in lipoprotein uptake, e.g., SRB1, LDLR, VLDLR, LRP1 and LPL, among others
(Ramasamy 2014). Wassef and colleagues studied the placental uptake of a single
dose of β-carotene delivered to pregnant mice at mid-gestation via intraperitoneal
injection (Wassef et al. 2012, 2015) in order to circumvent the high mouse intestinal
BCO1 cleavage activity (Widjaja-Adhi et al. 2015; Harrison 2012). This method
yielded variable but detectable amounts of intact β-carotene in the maternal bloodstream, as in humans (Grune et al. 2010). Moreover, this β-carotene was taken up
by the placenta (Kim et al. 2011; Wassef et al. 2012, 2013). In the placentas of βcarotene-supplemented wild-type dams maintained throughout life and gestation on
a VA-sufficient diet, the transcription of Lrp1 and Vldlr (but not of Lpl, Srb1 and
Ldlr), was down-regulated upon maternal β-carotene administration (Wassef et al.
2012, 2015). Although protein levels were not assessed in these studies, these findings
suggest the existence of a potential feedback mechanism that hinders the placental
β-carotene uptake when dietary VA intake is sufficient. Note that, although Lpl, Srb1
and Ldlr mRNA levels were not altered, one cannot exclude that these regulators play
a role in placental β-carotene uptake under other maternal dietary conditions (e.g.,
extensive pro-VA supplementation, consumption of diets containing different levels
of VA, or food deprivation). Nevertheless, experiments with LDLR knockout mice
maintained on a regular chow diet and injected with a single dose of β-carotene clearly
ruled out LDLR as a key mediator of β-carotene uptake by the placental-fetal unit
43
form and reach the developing embryo to serve as a source of VA for in situ synthesis of retinoids by the action of BCO1. Specifically, β-carotene supplementation of
BCO1
−/− RBP
−/− dams bred on the VA-deficient diet improved the retinoid levels
and congenital malformations of their BCO1
+/− RBP
−/− embryos (Kim et al. 2011).
Kim and colleagues also demonstrated that, aside from cleaving β-carotene to generate retinoids, embryonic BCO1 performs additional functions in retinoid and lipid
metabolism by modulating the esterification of retinol, cholesterol and diacylglycerols (Kim et al. 2015; Dixon et al. 2014). Although it has not been elucidated whether
this is a carotenoid-independent action of BCO1, this work confirmed the existence
of cross-talk between carotenoid and lipid metabolism (Kim et al. 2011; Palczewski
et al. 2016; Lee et al. 2014). This metabolic interaction could be particularly important during embryogenesis, given the critical role of lipids in proper development,
especially of the central nervous system (Haas and Muenke 2010; Farese et al. 1995,
1996). Other reports, some of which will be discussed below, further highlighted this
micro-macronutrient interaction and clearly indicated a novel avenue of research to
pursue in the future.
Regarding the transfer of β-carotene from the maternal to the fetal circulation
across the placenta, Quadro and colleagues hypothesized that this process depended
on lipoprotein metabolism, because β-carotene is transported in the adult bloodstream by lipoproteins [reviewed in (Parker 1996; Harrison 2012; Erdman et al.
1993)]. Moreover, the placenta acquires, assembles and secretes lipoproteins both
in vivo and in vitro (Kamper et al. 2015; Madsen et al. 2004). Serum β-carotene is
incorporated into chylomicrons, chylomicron remnants, VLDL, LDL, and even HDL
particles [reviewed in (Parker 1996; Harrison 2012; Erdman et al. 1993)]. Therefore,
its tissue uptake was hypothesized to be mediated by the same key regulators involved
in lipoprotein uptake, e.g., SRB1, LDLR, VLDLR, LRP1 and LPL, among others
(Ramasamy 2014). Wassef and colleagues studied the placental uptake of a single
dose of β-carotene delivered to pregnant mice at mid-gestation via intraperitoneal
injection (Wassef et al. 2012, 2015) in order to circumvent the high mouse intestinal
BCO1 cleavage activity (Widjaja-Adhi et al. 2015; Harrison 2012). This method
yielded variable but detectable amounts of intact β-carotene in the maternal bloodstream, as in humans (Grune et al. 2010). Moreover, this β-carotene was taken up
by the placenta (Kim et al. 2011; Wassef et al. 2012, 2013). In the placentas of βcarotene-supplemented wild-type dams maintained throughout life and gestation on
a VA-sufficient diet, the transcription of Lrp1 and Vldlr (but not of Lpl, Srb1 and
Ldlr), was down-regulated upon maternal β-carotene administration (Wassef et al.
2012, 2015). Although protein levels were not assessed in these studies, these findings
suggest the existence of a potential feedback mechanism that hinders the placental
β-carotene uptake when dietary VA intake is sufficient. Note that, although Lpl, Srb1
and Ldlr mRNA levels were not altered, one cannot exclude that these regulators play
a role in placental β-carotene uptake under other maternal dietary conditions (e.g.,
extensive pro-VA supplementation, consumption of diets containing different levels
of VA, or food deprivation). Nevertheless, experiments with LDLR knockout mice
maintained on a regular chow diet and injected with a single dose of β-carotene clearly
ruled out LDLR as a key mediator of β-carotene uptake by the placental-fetal unit