The goal of this project is to investigate the role of carnitine in placental function and fetal development. Carnitine is not only essential for transport of long-chain fatty acids into mitochondria for Beta-oxidation but also known to have other essential biological functions. The importance of carnitine is underscored by the clinical consequences associated with earnitine deficiency in humans. Primary carnitine deficiency due to defects in the Na+-coupled carnitine transporter (OCTN2) and secondary carnitine deficiency due to defects in fatty acid oxidation (FAO) compromise the functions of multiple organs including heart, skeletal muscle, and liver. Most of the studies of carnitine deficiency however have focused on clinical consequences in postnatal life. Very little is known at present on the effects of camitine deficiency during embryonic and fetal development. But, there are clear indications that carnitine plays a critical role in fetal development and placental function. Fetus accumulates camitine via effective transplacental transfer of maternal earnitine. OCTN2 is expressed in placenta and carnitine levels in placenta are higher than in any other maternal and fetal tissue. FAO plays an essential role in placental energy metabolism and FAO defects are associated with intrauterine growth retardation. These findings form the basis for the current project. Proposed studies will utilize normal human term placentas and three different mouse models (one model for primary carnitine deficiency and two models for secondary carnitine deficiency).
In specific aim 1, the influence of primary and secondary carnitine deficiencies on litter size, placental and fetal weight, and carnitine levels in placenta and embryo will be investigated using the mouse models.
In specific aim 2, the mechanism of transplacental transfer of camitine will be investigated in human placenta by analyzing carnitine transport processes in placental choriocarcinoma cells and in purified placental brush border and basal membrane vesicles.
In specific aim 3, the ability of human and mouse placentas to synthesize carnitine endogenously will be examined.
In specific aim 4, the role of carnitine in the biosynthesis of docosahexaenoic acid (DHA) in placental and fetal tissues will be investigated. DHA is an important fatty acid essential for the function of excitable tissues and there is evidence that carnitine plays a critical role in DHA biosynthesis. Use of murine models of carnitine deficiency will provide definitive information on the role of carnitine in DHA synthesis and also on the potential role of placenta as a source of DHA for the fetus.
In specific aim 5, the influence of camitine deficiency on gene expression in placental and fetal tissues will be investigated using the murine models. These studies will provide important information on the role of carnitine in placental and fetal development and lead to new therapeutic strategies to optimize fetal growth under various physiological and pathological conditions.
|Shekhawat, Prem S; Sonne, Srinivas; Matern, Dietrich et al. (2018) Embryonic lethality in mice due to carnitine transporter OCTN2 defect and placental carnitine deficiency. Placenta 69:71-73|
|Shekhawat, Prem S; Sonne, Srinivas; Carter, A Lee et al. (2013) Enzymes involved in L-carnitine biosynthesis are expressed by small intestinal enterocytes in mice: implications for gut health. J Crohns Colitis 7:e197-205|
|Sonne, Srinivas; Shekhawat, Prem S; Matern, Dietrich et al. (2012) Carnitine deficiency in OCTN2-/- newborn mice leads to a severe gut and immune phenotype with widespread atrophy, apoptosis and a pro-inflammatory response. PLoS One 7:e47729|
|Srinivas, Sonne R; Prasad, Puttur D; Umapathy, Nagavedi S et al. (2007) Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). Am J Physiol Gastrointest Liver Physiol 293:G1046-53|
|Baisden, B; Sonne, S; Joshi, R M et al. (2007) Antenatal dexamethasone treatment leads to changes in gene expression in a murine late placenta. Placenta 28:1082-90|
|Shekhawat, Prem S; Srinivas, Sonne R; Matern, Dietrich et al. (2007) Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2(-/-)) mice. Mol Genet Metab 92:315-24|
|Shekhawat, Prem S; Matern, Dietrich; Strauss, Arnold W (2005) Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. Pediatr Res 57:78R-86R|