The human genetic code is 99.9 percent identical. What makes people individuals, genetically speaking, equates to .1 percent of their individual genetic make-up and accounts for thousands of differentiations at the molecular level.
Deciphering those differentiations or polymorphisms and their involvement in the development of disease is the work of scientists like Karen Corbin, PhD, RD, and Brian Bennett, PhD, both with the UNC Chapel Hill Nutrition Research Institute (NRI) at the North Carolina Research Campus in Kannapolis. They are zeroing in on the specific genetic variations that will explain biological mechanisms that cause two seemingly unrelated diseases- fatty liver and atherosclerosis.
Genes, Metabolites and the Heart
Atherosclerosis, more commonly known as hardening of the arteries, is the focus of Bennett’s research. He studies genetic variants, gene expression levels and metabolite levels and how they increase or decrease a person’s susceptibility to cardiovascular disease. He particularly studies the metabolite Trimethylamine-N-oxide or TMAO, a metabolite of the essential nutrient choline.
Recent studies published in Nature Medicine and the New England Journal of Medicine strengthened the connection between TMAO as a cause and predictor of heart disease. Bennett’s interest in TMAO extends along similar lines.
“We know so much about the process of heart disease,” Bennett commented. “We really want to work upstream in that process to understand novel processes that aid in our detection of heart disease. By the time there is massive atherosclerosis, it’s a little bit late.”
One of the specific genes Bennett studies is the Farnesoid X Receptor (FXR). FXR is a regulator of TMAO and is expressed in the liver and intestine. The gene is involved with metabolizing cholesterol and the production of bile acids.
Nutrition, the Liver and Disease
The production of bile acids is relevant to the development of fatty liver disease, which Corbin studies.
“Something that has come up in my work with fatty liver is that bile acids are important signaling molecules that influence fatty liver. I’ve been working with this gene called FXR,” she said, “Brian, totally unbeknownst to me, was working on a study for the last four years where one of the genes that they found that regulates TMAO levels is FXR. So we converged at this gene looking at it for totally different reasons.”
Corbin researches fatty liver, which is the accumulation of excess fat on the liver, in terms of diet and nutrition, particularly dietary intake of the nutrient choline. Fatty liver is a health risk because too much fat on the liver can disrupt its ability to metabolize lipids or fats in the blood as well as other nutrients. Her goal is to determine causes and potential treatments for the disease that can prevent its progression to cirrhosis or liver cancer.
Fatty liver is also linked to another set of diseases known as metabolic syndrome. Metabolic syndrome is the presence of a number of health conditions such as high blood pressure, insulin resistance, atherosclerosis, diabetes, obesity and high cholesterol. Each one is linked to dietary and lifestyle choices and increased risk of heart disease, stroke or other chronic health problems.
Genetic Convergence At FXR
With metabolic and genetic connections, Corbin and Bennett are pursuing joint research to study the expression and the regulation of the FXR gene, novel genetic markers and the interaction of diet and genetics on the liver and heart. The study they designed employs a specialized set of mice called a collaborative cross which will be used to model fatty liver in humans. “Collaborative cross mice have a lot of genetic diversity,” Corbin said. “So it is almost like doing a human study because they mirror the diversity that is within humans.”
The study involves a dietary intervention to promote fatty liver. “Because of the genetic diversity,” Corbin explained, “some of the mice are going to be very sensitive to the diet and develop high levels of liver fat whereas other mice will be totally fine. We will then be able to figure out what makes these mice differentially susceptible to fatty liver. Then we can look at how we can address those same genetic markers in humans. It’s a very simple experiment, but it has the potential to be quite useful in pointing out more genetic markers.”
For Bennett, understanding the development of fatty liver gives him insight into the mechanisms that lead to atherosclerosis. “There is so much metabolism that occurs in the liver that it is a primary site of study,” he said. “It is also important to things like diabetes and insulin resistance and all of these happen before atherosclerosis or around the same time.”
Although choline is a nutrient that is a primary focus of study at the NRI, the genome wide approach of Corbin and Bennett’s research will facilitate the identification of a broader range of genes, metabolic pathways and nutrients and how they interact in the formation of disease. The goal, Corbin continued, is to “understand mechanisms that contribute to susceptibility of disease.”
For more information, visit www.uncnri.org.