Activation of Proneuronal Transcription Factor Ascl1 in Maternal Liver Ensures a Healthy Pregnancy

Abstract

How the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression of Ascl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring. BACKGROUND & AIMS:Maternal liver shows robust adaptations to pregnancy to accommodate the metabolic needs of the developing and growing placenta and fetus by largely unknown mechanisms. We found that Ascl1, a gene encoding a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice. METHODS: To investigate whether and how Ascl1Q7 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from midgestation until term.RESULTS: As a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 showed aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and increased release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta showed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 showed robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments. CONCLUSIONS:In summary, we show that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies show that Ascl1 is a novel and critical regulator of the physiology of pregnancy.

Ganoderic acids-rich ethanol extract from Ganoderma lucidum protects against alcoholic liver injury and modulates intestinal microbiota in mice with excessive alcohol intake

“…Therefore, inhibiting the expression of liver ACC1 , CD36 , C/EBP-α and SREBP-1c is beneficial to prevent the excessive accumulation of liver fatty acids. ASCL1 is involved in the shift of PPARα activation, and it well known that PPARα is a mainly modulator in the β-oxidation of fatty acids by regulating the mRNA expression of ACOX1 (a lipid-oxidation enzyme) ( Huang et al, 2020 ; Lee et al, 2021b ). The main function of ACSL1 is to promote the transfer of fatty acids as well as the synthesis of triacylglycerol, and determine the intake of exogenous fatty acids from adipose tissue ( Zhao et al, 2020 ).…”

Hepatological coordination of pregnancy-related changes

“…Although the role of altered production of sex hormones is well recognized to initiate the organ adaptations involved, remarkably little is known about the molecular mechanisms that mediate the changes in the mother. Remarkably, in the current issue of Cellular and Molecular Gastroenterology and Hepatology , Lee et al 1 show that the maternal liver plays a coordinating role in preparing the body of the mother for a successful pregnancy. The contribution of the liver in mediating pregnancy-associated changes that was uncovered by Lee et al 1 is surprisingly broad.…”

“…Remarkably, in the current issue of Cellular and Molecular Gastroenterology and Hepatology , Lee et al 1 show that the maternal liver plays a coordinating role in preparing the body of the mother for a successful pregnancy. The contribution of the liver in mediating pregnancy-associated changes that was uncovered by Lee et al 1 is surprisingly broad. It involves, apart from the liver itself, the maternal pancreas, spleen, kidney, placenta, and even the composition of the microbiome, among other effects in the expecting mother.…”

“…Central to the paper by Lee et al 1 is the transcription factor achaete-scute homolog-like 1 (Ascl1). This transcription factor is conventionally associated with compartment expansion in the developing neural system, probably through noncell autonomous activation of Notch signaling in neuroblasts, but is also implicated in oncogenesis of various endodermal derivatives.…”

“…The clarification of the identities and specific roles of these mediators should add to the understanding of the unexpected role, executed by the liver in ensuring a healthy pregnancy. Disregarding the currently incomplete insight into the exact details of the liver in controlling pregnancy-associated changes in the expecting mother, it is evident from the study published in the current issue of Cellular and Molecular Gastroenterology and Hepatology that Lee et al 1 have uncovered a very important novel functionality of the liver in the reproduction of mammals.…”