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Kim Colavito Markesich
University of Connecticut College of Agriculture and Natural Resources Journal April/May/June 2004

 

A grant proposal by Molly McGrane, associate professor of nutritional sciences, has been ranked as the top proposal nationwide for the USDA National Research Initiative’s program Improving Human Nutrition for Optimal Health.

McGrane’s application, entitled “Vitamin A Regulation of Gene Expression in Liver: From a Single Gene to a Multi-Gene Profile,” proposes to examine the mechanism by which vitamin A regulates gene expression in liver cells. Vitamin A is absorbed from food into the body via the gastrointestinal tract and transported throughout the body. Vitamin A eventually reaches liver cells, where its metabolites enter the nucleus and regulate target genes. “Vitamin A basically turns on the expression of numerous metabolic genes,” says McGrane.

She continues, “This is pretty exciting in the field of molecular nutrition. The liver is very important as it is the regulatory organ that maintains vitamin A at normal levels in the body and adequate vitamin A may be required for the liver to function to its full metabolic capacity.”

Working with McGrane in this study are senior Ph.D. student Kelly Scribner, who will take a postdoctoral fellowship at Harvard University next fall; Gautam Reddy, an M.S. student moving on to an internship at the UConn Health Center; and Ph.D. students Hye Won Kang and Pierre-Jacques Brun.

Previous studies showed that vitamin A regulates the expression of genes involved in vitamin A utilization and metabolism within the body. However, McGrane’s latest discovery shows that vitamin A also regulates genes involved in carbohydrate and lipid metabolism.

“This is a whole new category of genes. Prior to our work, no one thought vitamin A would be involved in these processes,” McGrane notes. “The old model had nutrients affecting hormone levels, which in turn changed gene expression. Twenty years ago nobody knew that nutrients got into the nucleus of the cell and interacted directly with the DNA of specific genes.”

Using a mouse model, McGrane found that when vitamin A is deficient, carbohydrate and lipid metabolism is altered and genes involved in carbohydrate and lipid metabolism have altered expression patterns; some genes are inhibited and some are stimulated above normal levels. Also, there are increased fat stores in the form of triglycerides and increased glycogen storage within the liver. McGrane anticipates that these elevated levels of liver fat will correlate with decreased liver function. 

While vitamin A deficiency is uncommon in the United States, it is not unheard of in certain populations, such as those with alcohol dependency. And, vitamin A deficiency is a severe health problem in underdeveloped countries, often resulting in night blindness and subsequent total blindness. To date, the additional problem of altered metabolism in these people has not been considered.

In the second part of the study, McGrane is using new technology to screen a large number of liver genes to see which are regulated by vitamin A. “It used to be that we measured one gene at a time,” says McGrane. “Now we have the ability to screen thousands of genes at a time through DNA microarray analysis.”

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

McGrane is fascinated by the connection between what happens at the molecular level and what is seen by clinicians. She says, “I have an interest in documenting the molecular mechanism and linking that to the clinical symptoms. If you can better identify what is going on at the molecular and metabolic level, it may be easier to diagnose when nutrient deficiencies are the cause of certain critical symptoms.”