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Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome
Marine Baptissart1, Christine M Bradish1, Brie S Jones1
1Department of Biological SciencesCenter for Human Health and the EnvironmentNorth Carolina State UniversityRaleighNorth CarolinaUSA.
Insights
Maternal metabolic syndrome (MetS) during postnatal development programs juvenile nonalcoholic fatty liver disease (NAFLD) in mice. Imprinted genes, regulated by Zac1, drive liver fibrosis, highlighting a critical pathway for metabolic disease programming.
Area of Science:
- Hepatology and Developmental Biology
- Epigenetics and Metabolic Disease
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a growing concern in children, predicted to be the leading cause of liver failure.
- Maternal metabolic syndrome (MetS) during early life can predispose offspring to juvenile NAFLD, but mechanisms remain unclear.
- Imprinted genes are hypothesized to mediate this susceptibility due to their environmental sensitivity and role in liver homeostasis.
Purpose of the Study:
- To investigate the role of imprinted genes in maternal MetS-induced juvenile NAFLD.
- To identify critical developmental periods for MetS exposure impacting NAFLD.
- To elucidate the molecular pathways linking maternal MetS to NAFLD pathogenesis.
Main Methods:
- Established a mouse model to assess MetS effects during prenatal vs. postnatal development.
- Utilized RNA sequencing to analyze gene expression changes in juvenile livers.
- Employed chromatin immunoprecipitation to study Zac1 binding to target gene promoters.
- Investigated the impact of Zac1 overexpression in vitro and in vivo.
Main Results:
- Postnatal MetS exposure, not prenatal, induced NAFLD hallmarks (steatosis, fibrosis) in juvenile mice.
- The Imprinted Gene Network (IGN), including Zac1, was significantly upregulated.
- Zac1 overexpression in hepatocytes induced profibrotic gene expression and liver fibrosis in vivo.
- Zac1 directly binds TGF-β1 and COL6A2 promoters, linking IGN to NAFLD pathophysiology.
Conclusions:
- Maternal MetS during postnatal development programs juvenile NAFLD via imprinted genes.
- Imprinted genes, particularly Zac1, are central players in metabolic disease programming.
- Identified a novel pathway linking maternal metabolic health to offspring liver disease.
Background And Aims:
Within the next decade, NAFLD is predicted to become the most prevalent cause of childhood liver failure in developed countries. Predisposition to juvenile NAFLD can be programmed during early life in response to maternal metabolic syndrome (MetS), but the underlying mechanisms are poorly understood. We hypothesized that imprinted genes, defined by expression from a single parental allele, play a key role in maternal MetS-induced NAFLD, due to their susceptibility to environmental stressors and their functions in liver homeostasis. We aimed to test this hypothesis and determine the critical periods of susceptibility to maternal MetS.
Approach And Results:
We established a mouse model to compare the effects of MetS during prenatal and postnatal development on NAFLD. Postnatal but not prenatal MetS exposure is associated with histological, biochemical, and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA sequencing, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up-regulated and overrepresented among differentially expressed genes, consistent with a role in maternal MetS-induced NAFLD. In support of this, activation of the IGN in cultured hepatoma cells by overexpressing Zac1 is sufficient to induce signatures of profibrogenic transformation. Using chromatin immunoprecipitation, we demonstrate that Zac1 binds the TGF-β1 and COL6A2 promoters, forming a direct pathway between imprinted genes and well-characterized pathophysiological mechanisms of NAFLD. Finally, we show that hepatocyte-specific overexpression of Zac1 is sufficient to drive fibrosis in vivo.
Conclusions:
Our findings identify a pathway linking maternal MetS exposure during postnatal development to the programming of juvenile NAFLD, and provide support for the hypothesis that imprinted genes play a central role in metabolic disease programming.
