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How high fructose intake may trigger fatty liver disease

A team of researchers supported by the NIDDK, as well as other NIH Institutes, discovered that consuming high amounts of fructose may promote nonalcoholic fatty liver disease by damaging the intestinal barrier, which leads to inflammation and effects on the liver. Fructose is a common type of sugar in the American diet, including its processed form called high-fructose corn syrup that is used to sweeten a variety of foods. Studies have linked excessive consumption of high-fructose corn syrup and other added sugars to health problems like obesity, diabetes, heart disease, and nonalcoholic fatty liver disease (NAFLD), in which too much fat is stored in liver cells. Fatty liver disease can lead to liver inflammation and liver damage, resulting in a more aggressive disease called nonalcoholic steatohepatitis (NASH) that can progress to scarring of the liver (cirrhosis), liver cancer, and liver failure. Scientists have been unsure how high fructose consumption might contribute to NAFLD.

A research team set out to explore fructose’s role in NAFLD. The researchers gave male mice either a high-fructose diet or a control diet with equivalent calories from corn starch, which breaks down into glucose, the sugar cells use for energy. Within a few months, mice on the high-fructose diet developed fatty livers and had greater rates of liver tumors than mice on the control diet. Mice bred to be prone to develop NASH showed clinical signs of the disease on the high-fructose diet. The team found that mice fed the high-fructose diet for long periods showed not only liver inflammation, but also deterioration of their intestinal barrier, which normally prevents bacteria and toxins in the gut from leaking into the bloodstream. Mice fed a high-fructose diet also had higher circulating levels of endotoxins—toxins released from certain bacteria when they die. The team discovered that leaked endotoxins prompted immune cells in the liver called macrophages to react and increase the production of cell signaling proteins like tumor necrosis factor (TNF) that can cause inflammation. Further experiments showed that these signaling proteins boosted enzymes that convert fructose into fatty deposits in the liver. Restoring the mice’s intestinal barrier prevented this fatty buildup in the liver. Using drugs and genetic manipulations, the team was able to stop the gut barrier deterioration from excessive fructose intake and prevent the onset of severe fatty liver disease and liver tumors. Experiments in human liver cells showed that a similar cellular process could take place in people: adding TNF to the human liver cells increased the conversion of fructose into fat.

Overall, this study points to a pathway in which high fructose levels could trigger a breakdown in the intestinal barrier and leakage of gut microbial products into the liver, thereby exacerbating inflammation and boosting the conversion of fructose into fatty deposits. The findings from this study could lead to new ways to treat and prevent NAFLD, which affects an increasingly large percentage of the U.S. population. For example, future studies could test agents that restore the integrity of the intestinal barrier in people at risk for NAFLD.

Todoric J, Di Caro G, Reibe S,…Karin M. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab 2: 1034-1045, 2020.

(Information adapted from original article by Ms. Erin Bryant, published on September 15, 2020, in NIH Research Matters.)

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