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“One thing we were very curious about was whether nonalcoholic fatty liver disease has a genetic underpinning,” says Hobbs. As part of the study, Hobbs and her colleagues used a special type of magnetic resonance imaging (MRI) scan to quantify liver fat in 2,349 participants. If the liver fat content was greater than 5.5 percent, the participant was classified as having NAFLD; about one-third of the total population fit the diagnosis.
“The biggest surprise for us wasn’t the incidence—we had suspected it would be high,” says Hobbs. “It was the differences among races.”
Among Hispanics, her team found, 45 percent had NAFLD. But only 33 percent of European Americans met the diagnosis criteria, and only 24 percent of African Americans had NAFLD. Even when they factored in obesity and diabetes, there were still major differences in the rate of NAFLD among ethnic groups.
Hobbs and her colleagues delved into genetic data from the patients and tested whether any genetic mutations could explain the different frequencies of NAFLD. They discovered that one variant of a gene called PNPLA3 seemed to predispose people to fatty liver. Moreover, the gene variant was most common in Hispanics, and least common in African Americans. It explained more than 70 percent of the differences in NAFLD incidence between races.
“Within all populations studied to date, the variation has been associated with fatty liver,” Hobbs says. “If you have the risk allele of the gene, you tend to have higher triglyceride content in the liver.”
In the liver, the PNPLA3 protein is responsible for breaking down triglycerides, the main building block of fats. So Hobbs suspected that the variant of PNPLA3 stopped the protein from working, or from being expressed at all in the liver, which would lead to an accumulation of fats. In mouse studies, however, her team has shown that an excess of the variant PNPLA3 protein causes fatty liver. Hobbs’ team is working to flesh out the mechanism involved. Solving the mystery will help uncover the biochemical pathways involved in fatty liver disease progression, but it’s unlikely to explain the full story of fatty liver.
“This is a gene-environment interaction,” says Hobbs. “If you have this gene and you’re thin, you won’t have fatty liver disease. But if you have this gene and you’re obese, it is very likely you will.”
The Diabetes Link
Even if there’s a genetic component to NAFLD, that doesn’t explain the increase in rates. The change in incidence can most likely be tracked back to changes in people’s diets—particularly an increase in sugar consumption—over the past few decades, says Loomba, whose San Diego clinic sees hundreds of NAFLD patients a year.
“If you take any normal, healthy person and do an MRI of their liver, and then start giving them three cans of soda a day, you can scan their liver again two weeks later and see liver fat already going up.”
Soda doesn’t have fat in it, but a diet high in sugar changes the way the body deals with nutrients, including fat. Normally, the hormone insulin produced by the pancreas after eating a meal causes the liver to store sugars—taken up from the blood in the form of glucose and fructose—for later (see diagram). And some of the glucose is repackaged into fat molecules. But a diet high in sugar can lead to insulin insensitivity, or insulin resistance. The body, including the liver, becomes less efficient at responding to insulin’s signals. Eventually, it stops responding at all. And rather than send the fat molecules into the blood, the liver retains the fat it produces.
When you eat, insulin produced by the pancreas puts your body into storage mode to save all the energy you’ve ingested (left side of diagram). in the liver, glucose is converted to glycogen for long-term storage. in fat deposits around the body, molecules come together to form fats. and in muscles, the building blocks of proteins assemble. once you’ve digested the food, glucose and insulin levels drop and the molecules that have been assembled for energy storage start being broken down as your body needs them.
“The liver is clearly central to normal glucose homeostasis,” says Shulman, who is determined to sort out the intricate interplay between sugar and fat metabolism in the liver. The critical questions, he says, are what factors lead to the development of NAFLD and how do alterations in the liver’s metabolism of fat contribute to insulin resistance in the liver.
Illustration: Graham Roumieu