"NAFLD is the most common cause of chronic liver disease in the world. It can progress to more serious conditions, such as cirrhosis, liver cancer, liver failure and death," said senior author Michael Karin, Ph.D., Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine, in a press release. "These findings point to an approach that could prevent liver damage from occurring in the first place."
Fructose consumption in the U.S. has skyrocketed since the introduction of high fructose corn syrup (HFCS). Multiple studies, the press release notes, have linked increased HFCS consumption with the nation’s obesity epidemic and inflammatory conditions including diabetes and heart disease.
FDA regulates it just fructose similarly to other sweeteners, like sucrose and honey—but this study, published inNature Metabolism, defines a specific role for HFCS in the development of NAFLD. Fructose is broken down in the human digestive tract by an enzyme called fructokinase, produced both by the liver and the gut. In mouse models, researchers found that excessive fructose metabolism in intestinal cells reduces production of proteins that maintain the gut barrier, a layer of tightly packed epithelial cells covered with mucus that prevents bacteria and microbial products, such as endotoxins, from leaking out of the intestines and into the blood.
"Thus, by deteriorating the barrier and increasing its permeability, excessive fructose consumption can result in a chronic inflammatory condition called endotoxemia, which has been documented in both experimental animals and pediatric NAFLD patients," said the study's first author Jelena Todoric, MD, PhD, a visiting scholar in Karin's lab, in the press release.
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In the study, Karin, Todoric, and colleagues from around the world found that leaked endotoxins reaching the liver provoked increased production of inflammatory cytokines and stimulated the conversion of fructose and glucose into fatty acid deposits.Another finding: When fructose intake was reduced below a certain threshold, no adverse effects were observed in mice, suggesting that only excessive and long-term fructose consumption represents a health risk. Moderate fructose intake through fruits is well-tolerated.
"Unfortunately, many processed foods contain HFCS and most people cannot estimate how much fructose they actually consume," said Karin. "Although education and increased awareness are the best solutions to this problem, for those individuals who had progressed to the severe form of NAFLD known as nonalcoholic steatohepatitis, these findings offer some hope of a future therapy based on gut barrier restoration."
