Neeraja Purandare1, Paige Minchella1, Mallika Somayajulu1, Katherine J Kramer2, Jordan Zhou1, Nellena Adekoya3, Robert A Welch4, Lawrence I Grossman1, Siddhesh Aras1, Maurice-Andre Recanati5. 1. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA. 2. Department of Obstetrics and Gynecology, St. Vincent's Medical Centers Manhattan, New York, NY, 10011, USA. 3. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA. 4. Department of Obstetrics and Gynecology, School of Human Medicine, Michigan State University, Hurley Medical Center, Flint, MI, 48503, USA. 5. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, 48201, USA. Electronic address: marecanati@wayne.edu.
Abstract
INTRODUCTION: Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) is necessary for surfactant production in fetal lungs. Mechanisms responsible for its regulation during gestation remain to be elucidated. Our goal is to evaluate molecular mechanisms regulating LPCAT1 expression during gestation and after glucocorticoid administration. METHODS: Placentas throughout gestation were assayed for LPCAT1 protein levels. A placental cell line, HTR-8/SVneo (HTR), was used as a model to test the effects of placental oxygen tension found during pregnancy as well as the effects of dexamethasone used therapeutically in the clinic. RESULTS: LPCAT1 protein levels are maximal in late third trimester placental samples and are expressed strongly on the basal plate. LPCAT1 was maximally upregulated at 4% O2 (P < 0.01), corresponding to oxygen tension found in placenta at term. Mitochondrial nuclear retrograde regulator 1 (MNRR1), a bi-organellar (mitochondria and nucleus) regulator, transcriptionally activates LPCAT1. Antenatal corticosteroids (ACS) upregulate LPCAT1, at least in part, by an MNRR1-dependent pathway. HTR cells treated with 25 nM dexamethasone for 24 h exhibited a 2-fold increase in LPCAT1 levels compared to controls. In MNRR1 knockout cells, the response to ACS is significantly blunted. DISCUSSION: LPCAT1 appears to be induced by MNRR1. Hypoxia and corticosteroids increase LPCAT1 expression through an MNRR1 dependent pathway. LPCAT1 protein levels can be measured in maternal plasma and rise throughout gestation and in response to ACS.
INTRODUCTION: Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) is necessary for surfactant production in fetal lungs. Mechanisms responsible for its regulation during gestation remain to be elucidated. Our goal is to evaluate molecular mechanisms regulating LPCAT1 expression during gestation and after glucocorticoid administration. METHODS: Placentas throughout gestation were assayed for LPCAT1 protein levels. A placental cell line, HTR-8/SVneo (HTR), was used as a model to test the effects of placental oxygen tension found during pregnancy as well as the effects of dexamethasone used therapeutically in the clinic. RESULTS: LPCAT1 protein levels are maximal in late third trimester placental samples and are expressed strongly on the basal plate. LPCAT1 was maximally upregulated at 4% O2 (P < 0.01), corresponding to oxygen tension found in placenta at term. Mitochondrial nuclear retrograde regulator 1 (MNRR1), a bi-organellar (mitochondria and nucleus) regulator, transcriptionally activates LPCAT1. Antenatal corticosteroids (ACS) upregulate LPCAT1, at least in part, by an MNRR1-dependent pathway. HTR cells treated with 25 nM dexamethasone for 24 h exhibited a 2-fold increase in LPCAT1 levels compared to controls. In MNRR1 knockout cells, the response to ACS is significantly blunted. DISCUSSION: LPCAT1 appears to be induced by MNRR1. Hypoxia and corticosteroids increase LPCAT1 expression through an MNRR1 dependent pathway. LPCAT1 protein levels can be measured in maternal plasma and rise throughout gestation and in response to ACS.
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