44
L. Quadro and E. K. Spiegler
(Shete et al. 2016). Instead, this study revealed a significant contribution of LDLR
to hepatic β-carotene uptake, at least in pregnant females. It remains to be established whether LDLR is involved in placental β-carotene uptake under conditions of
prolonged pro-VA availability or different maternal VA statuses.
The placental uptake of β-carotene from the maternal circulation is, indeed,
dependent upon the maternal VA status. The placentas of LRAT
−/− RBP
/− mice
on a VA-sufficient diet (a mouse model of marginal VA deficiency) took up more
β-carotene than the placentas of wild-type mice (Wassef et al. 2012). However,
the local metabolism of the pro-VA carotenoid also depends on the maternal VA
status/intake and ultimately impacts the amount of β-carotene that can reach the
developing fetus. Wassef and colleagues (2015) showed that when wild-type dams,
maintained on a high-VA diet during pregnancy, were acutely supplemented with
β-carotene via intraperitoneal injection, the transfer of β-carotene to the embryo was
dramatically attenuated (embryonic β-carotene was undetectable) compared to dams
on a VA-sufficient diet. However, no difference was observed in placental β-carotene
accumulation. Remarkably, placental Lrp1, Vldlr and Bco1 were upregulated in βcarotene-injected dams fed the high-VA diet compared with the VA-sufficient diet.
Such data suggest that β-carotene is more efficiently taken up and cleaved to retinoids
in placentas from dams on an excess VA diet. A significant elevation in placental
Cyp26a1 expression was also seen in β-carotene-treated dams fed a higher dietary
VA content, suggesting that the generated RA is more efficiently catabolized when
VA is in excess. Therefore, the maternal diet seems to determine which metabolic
pathways are stimulated to ensure placental retinoid homeostasis and to regulate the
transfer of preformed VA and β-carotene (pro-VA) to the embryo.
Recent work by Costabile and colleagues (2016) has begun to shed light on the
mechanisms whereby, upon placental uptake, β-carotene is re-secreted towards the
fetal circulation. This process is mediated by placental lipoprotein secretion, which
in turn is regulated by β-apocarotenoids generated when β-carotene is asymmetrically cleaved by placental BCO2. The work of Costabile and colleagues suggests
that the mRNA expression (and probably activity) of Bco2 in the placenta is upregulated when β-carotene is available, such that the production of β-apo-10
carotenoids
from asymmetrically cleaved β-carotene increases. Then, either directly or indirectly,
these β-apo-10
carotenoids transcriptionally regulate the expression of microsomal
triglyceride transfer protein (Mttp) via hepatic nuclear factor 4α (Hnf4α) and chicken
ovalbumin upstream promoter transcription factor I/II (Coup-TFI and Coup-TFII).
Notably, the same regulatory mechanism was observed upon maternal supplementation of β-apo-10
carotenoids, clearly indicating that these compounds can be taken
up by and act within the placenta. Such data confirm the emerging notion that βapocarotenoids may function as transcriptional regulators that antagonize retinoid
signaling by binding to RAR and RXR (Eroglu et al. 2010, 2012; Sun et al. 2014;
Ziouzenkova et al. 2007; Wang et al. 2015; Costabile et al. 2016). They are also the
first in vivo evidence of the transcriptional regulatory activity of β-apocarotenoids.
MTP critically regulates the synthesis of lipoproteins by binding to lipids and
chaperoning them to nascent apolipoprotein B (apoB) so that aberrant folding and
L. Quadro and E. K. Spiegler
(Shete et al. 2016). Instead, this study revealed a significant contribution of LDLR
to hepatic β-carotene uptake, at least in pregnant females. It remains to be established whether LDLR is involved in placental β-carotene uptake under conditions of
prolonged pro-VA availability or different maternal VA statuses.
The placental uptake of β-carotene from the maternal circulation is, indeed,
dependent upon the maternal VA status. The placentas of LRAT
−/− RBP
/− mice
on a VA-sufficient diet (a mouse model of marginal VA deficiency) took up more
β-carotene than the placentas of wild-type mice (Wassef et al. 2012). However,
the local metabolism of the pro-VA carotenoid also depends on the maternal VA
status/intake and ultimately impacts the amount of β-carotene that can reach the
developing fetus. Wassef and colleagues (2015) showed that when wild-type dams,
maintained on a high-VA diet during pregnancy, were acutely supplemented with
β-carotene via intraperitoneal injection, the transfer of β-carotene to the embryo was
dramatically attenuated (embryonic β-carotene was undetectable) compared to dams
on a VA-sufficient diet. However, no difference was observed in placental β-carotene
accumulation. Remarkably, placental Lrp1, Vldlr and Bco1 were upregulated in βcarotene-injected dams fed the high-VA diet compared with the VA-sufficient diet.
Such data suggest that β-carotene is more efficiently taken up and cleaved to retinoids
in placentas from dams on an excess VA diet. A significant elevation in placental
Cyp26a1 expression was also seen in β-carotene-treated dams fed a higher dietary
VA content, suggesting that the generated RA is more efficiently catabolized when
VA is in excess. Therefore, the maternal diet seems to determine which metabolic
pathways are stimulated to ensure placental retinoid homeostasis and to regulate the
transfer of preformed VA and β-carotene (pro-VA) to the embryo.
Recent work by Costabile and colleagues (2016) has begun to shed light on the
mechanisms whereby, upon placental uptake, β-carotene is re-secreted towards the
fetal circulation. This process is mediated by placental lipoprotein secretion, which
in turn is regulated by β-apocarotenoids generated when β-carotene is asymmetrically cleaved by placental BCO2. The work of Costabile and colleagues suggests
that the mRNA expression (and probably activity) of Bco2 in the placenta is upregulated when β-carotene is available, such that the production of β-apo-10
carotenoids
from asymmetrically cleaved β-carotene increases. Then, either directly or indirectly,
these β-apo-10
carotenoids transcriptionally regulate the expression of microsomal
triglyceride transfer protein (Mttp) via hepatic nuclear factor 4α (Hnf4α) and chicken
ovalbumin upstream promoter transcription factor I/II (Coup-TFI and Coup-TFII).
Notably, the same regulatory mechanism was observed upon maternal supplementation of β-apo-10
carotenoids, clearly indicating that these compounds can be taken
up by and act within the placenta. Such data confirm the emerging notion that βapocarotenoids may function as transcriptional regulators that antagonize retinoid
signaling by binding to RAR and RXR (Eroglu et al. 2010, 2012; Sun et al. 2014;
Ziouzenkova et al. 2007; Wang et al. 2015; Costabile et al. 2016). They are also the
first in vivo evidence of the transcriptional regulatory activity of β-apocarotenoids.
MTP critically regulates the synthesis of lipoproteins by binding to lipids and
chaperoning them to nascent apolipoprotein B (apoB) so that aberrant folding and