A UConn study focusing on how vitamin A is necessary for the normal metabolic
function of the liver is the top national grant proposal in this year’s USDA
National Research Initiative program on improving human nutrition. The
review panel gave the proposal the top ranking among those submitted, and
awarded $300,000
to fund the study.

Mary (“Molly”) McGrane, an associate professor of nutritional sciences,
is conducting the study, which examines how vitamin A regulates gene expression
in liver cells. Gene expression is the process by which a gene’s coded information
is converted into a protein product that has a structural, functional, or regulatory
impact on a cell, an organ, or the whole body.

Molly McGrane, an associate professor of nutritional sciences, left,
looks over a DNA microarray used to review genes with Hyewon Kang, a doctoral student. Photo by Peter Morenus

The liver, which is the body’s largest solid organ, is the metabolic hub of
the human body.

“Having adequate vitamin A is required to have your liver function normally,” says
McGrane, “since it regulates the metabolism of carbohydrates, fats, and proteins.
Prior to our studies, we didn’t know that vitamin A had anything to do with
the regulation of carbohydrate, lipid, and – potentially – cholesterol
metabolism.”

Vitamin A is absorbed from food into the body via the small intestine and is
transported throughout the body. Eventually, metabolites of vitamin A reach the
nucleus of cells in the various tissues, including the liver, where they regulate
many target genes. Vitamin A is a fat-soluble vitamin found in animal sources such
as liver, fish, and milk or in beta-carotene plant sources such as carrots, tomatoes,
apricots, and spinach. The USDA recommended daily intake of vitamin A is 700 micrograms
for women and 900 micrograms for men.

“Traditionally, scientists didn’t think that nutrients got into the nucleus
of cells and interacted directly with the DNA and then affected the expression of
target genes,” McGrane says.

All cells in the body have exactly the same complement of genes – a liver
cell is made of the same information as a muscle cell, for example – yet cells
all perform different functions as they form into organs and parts of the body.

“Clearly the cells all work differently, and what causes those differences
is which genes are expressed and which genes are not,” she says. “The
process of turning the genes on and off has to be regulated, and we’re still
learning what the process of regulation is, but nutrients and their metabolites are
clearly among the regulatory molecules involved.”

Using mice for their studies, McGrane and her graduate student research assistants
compare the expression of thousands of genes in livers from vitamin A-sufficient
and
vitamin A-deficient mice. After documenting differential gene expression with
vitamin A deficiency, the metabolic disturbances linked to specific genes are examined.
To date, the changes observed show altered carbohydrate, fat, and cholesterol metabolism
in vitamin A-deficient liver.

A deficiency in vitamin A is rare in the United States – it is found primarily
in those with alcohol dependency – but it is not uncommon in underdeveloped
nations, where poor nutrition
is often an issue. Lack of the vitamin can cause blindness.

McGrane is being aided in her study by some new technology, which now allows
the screening of a large number of liver genes to determine which ones are regulated
by vitamin A. Thousands of genes can be reviewed simultaneously using a DNA micro-array
analysis.

“We’re hoping to identify the entire population of genes of carbohydrate
and fat metabolism regulated by vitamin A,” she says. “Once we identify
these genes we may be able to learn how they cause increased fat storage and other
changes in the liver.”

By documenting what happens at the molecular level, McGrane says, there is a
better chance that a link can be made to clinical symptoms of poor nutrition.