In mice, mothers with metabolic syndrome can 'turn on' offspring's liver disease

Date:
February 7, 2022
Source:
North Carolina State University
Summary:
An imprinted gene associated with development of non-alcoholic
fatty liver disease (NAFLD) is switched on in mice who nurse from
mothers with metabolic syndrome, even when those mice are not
biologically related.



FULL STORY ==========================================================================
New research from North Carolina State University has found that
an imprinted gene associated with development of non-alcoholic fatty
liver disease (NAFLD) is switched on in mice who nurse from mothers with metabolic syndrome, even when those mice are not biologically related. The finding supports the hypothesis that imprinted genes play important
roles in this metabolic disease, and could lead to the development of preventative treatments.


========================================================================== NAFLD is a condition where excess fat builds up in liver tissue for
reasons unrelated to alcohol consumption. If untreated, the excess fat
can lead to inflammation, scarring and increased risk of liver cancer. The incidence of NAFLD is increasing among children and adolescents, with 10%
of children in the U.S. currently affected. This number is expected to
increase within the next decade.

"We know that development of NAFLD is partly to do with 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 work.

Metabolic syndrome, or MetS, is a catchall term for a number of
health issues including high blood sugar, obesity and elevated blood
pressure. Previous studies had shown a link between MetS in mothers and increased NAFLD susceptibility in infants.

"We wanted to look specifically at mothers with MetS to see whether
infants are affected pre- or post-natally, and tease out what is happening
on the molecular level to trigger the disease," Cowley says.

In a mouse model of MetS, Cowley and his colleagues compared offspring
of mice with MetS to those from control mice, or mice without MetS. They studied four groups: offspring of control mice nursed by control mice, offspring of MetS mice nursed by MetS mice, and cross-fostered offspring
from both groups. Cross- fostered means that the offspring of one group
were nursed by mothers from the other group. They compared 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 from both 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 nursed by the MetS mothers.

Imprinted genes are a small set of genes which are expressed from a single parental allele. Most genes consist of two copies (one inherited from
each parent) which activate and influence inherited traits. Imprinted
genes are expressed by a single active copy, and have been shown to be susceptible to changes in environmental factors.

"Zac1 is acting as the master switch here," Cowley says. "It was activated
in pups that nursed from MetS mothers, and this has downstream effects
in the IGN that lead to an increased susceptibility to NAFLD.

"Researchers have proposed that imprinted genes play a role in this
process - - we're showing here that they do," Cowley continues. "The
work also confirms the post-natal environment is more important to the development of the disease than pre-natal exposure. Our next steps will
involve looking at what happens once potential environmental stressors
such as the mother's milk are removed.

Can Zac1 be switched off again?" The research appears in Hepatology
and was supported by the National Institutes of Health (grant numbers K22ES027510, R01ES031596, P30ES025128 and P30DK034987) and by Oak Ridge Associated Universities through a Ralph E. Powe Junior Faculty Enhancement Award. Marine Baptissart, former postdoctoral researcher at NC State,
is first author.

========================================================================== Story Source: Materials provided by
North_Carolina_State_University. Original written by Tracey Peake. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Marine Baptissart, Christine M. Bradish, Brie S. Jones, Evan
Walsh, Jesse
Tehrani, Vicmarie Marrero‐Colon, Sanya Mehta, Dereje D. Jima,
Seh Hoon Oh, Anna Mae Diehl, Tiffany Fougeray, Herve' Guillou,
Michael Cowley. Zac1 and the Imprinted Gene Network program juvenile
NAFLD in response to maternal metabolic syndrome. Hepatology,
2022; DOI: 10.1002/ hep.32363 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220207124845.htm

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