New research from North Carolina State University has found that a printed gene associated with the development of non-alcoholic fatty liver disease (NAFLD) is activated in mice that breastfeed from mothers with metabolic syndrome, even when those mice are not biologically linked. The finding supports the hypothesis that imprinted genes play an important role in this metabolic disease and could lead to the development of preventive treatments.
NAFLD is a condition in which excess fat builds up in liver tissue for reasons unrelated to alcohol consumption. If left untreated, excess fat can lead to inflammation, scarring, and an increased risk of liver cancer. The incidence of NAFLD is increasing in children and adolescents, with 10% of children in the United States currently affected. This number is expected to increase over the next decade.
“We know that the development of NAFLD is partly related to diet and lack of exercise, but there is an environmental component that primes an infant’s liver to develop it as well; specifically, the metabolic state of the mother,” says Michael Cowley, associate professor of biology at NC State and corresponding author of the book.
Metabolic syndrome, or MetS, is a catch-all term for a number of health conditions, including high blood sugar, obesity, and high blood pressure. Previous studies had shown a link between MetS in mothers and increased susceptibility to NAFLD in infants.
“We wanted to look specifically at mothers with MetS to see if infants are affected before or after birth, and unravel what’s going on at the molecular level to trigger the disease,” says Cowley.
In a mouse model of MetS, Cowley and colleagues compared the offspring of mice with MetS to that of control mice or mice without MetS. They studied four groups: the offspring of control mice breastfed by control mice, the offspring of MetS mice breastfed by MetS mice, and the crossbred offspring of the two groups. Cross-fostering means that offspring from one group were nursed by mothers from the other group. They compared the offspring at birth and at three weeks after birth, just before weaning.
They found that mice born to MetS mothers and nursed by control mice did not develop NAFLD, whereas most mice in the control and MetS groups nursed by MetS mothers did.
Using RNA sequencing, the researchers found that the imprinted gene network (IGN), including its regulator, an imprinted gene called Zac1, was upregulated, or more active, in mice fed MetS mothers. .
Imprinted genes are a small set of genes that are expressed from a single parental allele. Most genes consist of two copies (one inherited from each parent) that activate and influence inherited traits. Imprinted genes are expressed by a single active copy and have been shown to be sensitive to changes in environmental factors.
“Zac1 acts as the master switch here,” says Cowley. “It was activated in puppies nursing from MetS mothers, and it has downstream effects in the IGN that lead to increased susceptibility to NAFLD.
“Researchers have proposed that imprinted genes play a role in this process – we show here that they do,” Cowley continues. “The work also confirms that the postnatal environment is more important for the development of the disease than prenatal exposure. Our next steps will be to look at what happens once potential environmental stressors such as breast milk are eliminated. again ?”
The search appears in Hepatology and was supported by the National Institutes of Health (grant numbers K22ES027510, R01ES031596, P30ES025128, and P30DK034987) and Associated Oak Ridge Universities through a Ralph E. Powe Junior Faculty Enhancement Award. Marine Baptissart, a former postdoctoral researcher at NC State, is the first author.