New Genetic Approaches to Predict and Prevent Fatty Liver

New Genetic Approaches to Predict and Prevent Fatty Liver

December 20, 2012

When Karen Corbin, PhD, RD, first read the UNC Chapel Hill Nutrition Research Institute’s (NRI) mission- exploring nutritional individuality- she knew she’d found the place she could build her career.

As a clinical dietitian, certified diabetes educator and co-director of preventive services at the Heart and Vascular Institute of Florida from 1998 to 2003, Corbin saw first-hand how nutritional interventions for patients with diabetes, cardiovascular disease and obesity did not always generate the expected improvements in health. She came to the conclusion that the nutritional approaches available to treat those diseases did not account for biological differences such as genetics. This realization motivated her to pursue a doctorate degree and to make understanding nutritional individuality her life’s work.

Corbin learned about the NRI, which is located on the NC Research Campus (NCRC) in Kannapolis, while searching online for a postdoctoral position in nutrition research. She joined the institute in 2009 after completing her PhD in molecular medicine from the University of South Florida, College of Medicine. She joined the research team of NRI Director Steven Zeisel, MD, PhD.

Zeisel is a pioneer and leading expert in the study of the nutrient choline and its connection to human health and disease. Choline is an essential nutrient found in eggs, meats, nuts and legumes. Although the body can make choline, most people do not make enough to meet their needs. Zeisel’s research has proven that a lack of dietary choline leads to numerous health problems including fatty liver, liver damage and muscle damage.

“Once I started learning about choline and what Dr. Zeisel was doing, I realized there would be a link to those diseases (cardiovascular disease and diabetes) as well,” Corbin explained. “Actually, fatty liver is a major integrator of those diseases.  So I ended up choosing a project in fatty liver because I knew it had a relationship to the diseases I was most interested in studying.”

Corbin is researching genetic variations in the choline pathway that include intersecting pathways in folate, methionine, lipid and bile metabolism that are leading her to understand the physiological mechanisms that contribute to the development of non-alcoholic fatty liver disease (NAFLD). Her long-term goal is to identify individualized nutritional interventions that could help prevent and treat NAFLD and related disorders such as diabetes, obesity and cardiovascular disease. She is also interested in finding interventions that will lessen the incidence of progression of NAFLD into liver cancer.

Non-Alcoholic Fatty Liver Disease

NAFLD is an excess accumulation of fat in the liver. As fat accumulates, the organ’s ability to metabolize sugar, protein and fats is disrupted. The disruption can trigger a sequence of liver damage that begins with non-alcoholic steatohepatitis (NASH). NASH is an inflammatory state that can lead to cirrhosis, or scarring of the liver, which, in turn, may lead to liver cancer in some people.

As Corbin explained, the occurrence of NAFLD continues to rise worldwide in conjunction with the climbing rates of obesity, diabetes and metabolic syndrome, which is the combination of disorders like high blood pressure, high cholesterol and insulin resistance that increase the risk for developing cardiovascular disease, diabetes and stroke.  In fact, Corbin said, in the United States one in three people of normal weight and up to 96 percent of overweight or obese people have NAFLD. According to the National Heart, Lung and Blood Institute, a division of the National Institutes of Health, NAFLD is predicted to overtake smoking as the major risk factor for heart disease.
“Different from alcohol-induced fatty liver, where there is already an insult from the alcohol itself, NAFLD develops for other reasons that are not completely understood,” she commented. “Actually what is interesting is that a relatively small proportion of people who have fatty liver progress to liver cancer. When you have outliers like that, those are the people who are really interesting to study because if you can figure out what’s different about them then you can move towards understanding mechanism.”

What is also alarming, Corbin states, is that rates of liver cancer have increased dramatically in the US over recent decades, possibly suggesting that metabolic diseases such as obesity, diabetes and fatty liver are playing a much larger role in liver disease progression than previously believed.

Genetics to Predict Risk, Plan Interventions

To uncover the mechanisms responsible for NAFLD, Corbin is studying the genetic variations in the choline pathway and related pathways that are involved in metabolizing fat in the liver. Through collaborating with Duke University, she gained access to a biorepository of DNA and clinical information from liver biopsies from volunteers with risk factors for NAFLD. The samples represented the spectrum of liver health from those with no disease to those that were very diseased. With the help of others on the research team, a computational technique called hierarchical clustering was utilized to group subjects by patterns of genetic variations instead of by categories that ranked the amount of fat in the liver.  This novel way of looking at the genetic data helped uncover a genetic pattern in the choline pathway that could distinguish individuals with very low versus very high levels of liver fat. In addition, a genetic pattern was identified distinct to African Americans, who, as an ethnic group, have very low incidence of fatty liver. This work was accepted for publication in the Federation for American Societies for Experimental Biology Journal on December 18, 2012.

Corbin’s challenge now is to repeat the study in larger and more diverse populations and look for any additional  variations to help refine her model as a predictive tool for assessing who is at risk for fatty liver and its resulting complications like liver cancer.

“If we can do that from a genetic pattern, that is something that could be put into medical practice,” she said. “That is our end goal to see if we can develop this method to help us better asses risk for disease with genetics. If we can use genetics in a more predictive way, it might help us not just assess disease risk but assess what type of nutrition intervention might be most beneficial.”

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