Hepatological coordination of pregnancy-related changes

Autor: Maikel P. Peppelenbosch, Vincent T. Janmaat
Přispěvatelé: Gastroenterology & Hepatology
Jazyk: angličtina
Rok vydání: 2022
Předmět:
GD
gestation day
medicine.medical_specialty
IGF2R
IGF2 receptor
Ascl1
achaete-scute homolog-like 1
PL
placental lactogen
RC799-869
AKT
protein kinase B
P
promoter
cDNA
complementary DNA
ERK
extracellular signal-regulated kinase
Pregnancy
Humans
Medicine
Hepatocyte
Original Research
AAV8
adeno-associated virus 8
IGF2
insulin-like growth factor 2
Hepatology
business.industry
Obstetrics
RNA-seq
RNA sequencing
Gastroenterology
TBG-Cre
Cre recombinase under the control of hepatocyte-specific thyroxine-binding globulin promoter
ISH
in situ hybridization
Diseases of the digestive system. Gastroenterology
medicine.disease
mRNA
messenger RNA
qRT-PCR
quantitative reverse-transcription polymerase chain reaction
Insulin-Like Growth Factor 2
4E-BP1
eukaryotic translation initiation factor 4E-binding protein 1
Female
business
Gestation
Zdroj: CMGH, 13(1). Elsevier Inc.
Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 338-(2022)
Cellular and Molecular Gastroenterology and Hepatology
ISSN: 2352-345X
Popis: 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 Ascl1 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.
Graphical abstract
Databáze: OpenAIRE
Externí odkaz: