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October 5, 2017

Fructose Is Harder Than Glucose on Liver, If Diet Is Rich in Fat

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    Fructose can be more harmful than glucose, raising the risk of obesity, insulin resistance, and fatty liver disease. [NIH]

    Different sugars can have different metabolic effects, regardless of whether the sugars are consumed in calorically equal amounts. For example, fructose can be more harmful than glucose, raising the risk of obesity, insulin resistance, and fatty liver disease. Although such divergent fructose/glucose outcomes were not observed in mice that were fed an ordinary diet, metabolic outcomes in mice fed a high-fat diet were worse if the diet was supplemented with fructose, rather than glucose.

    This finding emerged from a study conducted by Joslin Diabetes Center scientists. The study also explored the biological processes behind the divergent fructose/glucose outcomes. Specifically, the scientists discovered that production of an enzyme called ketohexokinase (Khk), required for the first step of fructose metabolism, was increased in the livers of mice who drank fructose. When the scientists examined liver samples from obese human teenagers with fatty liver disease, they also found higher levels of Khk.

    The Khk enzyme is important in metabolizing fructose, a sugar found in sweetened beverages and many other processed foods, in high-fructose corn syrup, but it is not so important in metabolizing glucose, which is found in table sugar. Consequently, the scientists suspect that Khk might offer a target for clamping down on fructose metabolism.

    Detailed results from the study appeared October 3 in the Journal of Clinical Investigation, in an article entitled “Divergent Effects of Glucose and Fructose on Hepatic Lipogenesis and Insulin Signaling.” These divergent effects included physiological differences, such as the development of more or less pronounced obesity, glucose intolerance, and hepatomegaly. Divergent effects were also observed at the transcriptional and metabolomic levels.

    “Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP [carbohydrate-responsive element-binding protein] and SREBP1c [sterol regulatory element-binding transcription factor 1],” wrote the article’s authors. “While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling.”

    Over 10 weeks, none of the animals on a regular diet developed insulin resistance (a key factor in metabolic disease), although those consuming either form of sugar gained substantially more weight.

    Among animals on a high-fat diet, however, significant differences emerged between those drinking fructose and glucose.

    "Fructose was associated with worse metabolic outcomes," said Samir Softic, M.D., first author on the paper. Mice on the high-fat diet become much more obese and more insulin-resistant compared to their peers on the glucose diet. And while both groups of animals added fat to their livers, the fat composition was quite different.

    “Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation,” the article explained. “Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice.”

    Essentially, the study demonstrated that cells handle fructose and glucose very differently, a result that is relevant to the two billion people in the world who are overweight or obese, or the one billion people with fatty liver disease. Many of these people are already aware that they should cut calories—especially calories from concentrated sugars such as high-fructose corn syrup.

    Although fatty liver disease usually does not progress to dangerous levels of liver inflammation, the condition is an increasing concern as its rates climb in the worldwide obesity epidemic, noted Dr. Softic, who is a researcher in the laboratory of C. Ronald Kahn, M.D., and a pediatric gastroenterologist at Boston Children's hospital. Additionally, fatty liver disease has become a particular concern among children, Dr. Softic emphasized.

    To follow up on the possibility of targeting Khk, the Joslin team collaborated with researchers at Alnylam Pharmaceuticals in Cambridge, MA, to tamp down on production of the Khk protein in the liver. The treatment lowered liver weight and improved glucose tolerance among mice on any diet, but most strikingly among those on the high-fat/high-fructose diet.

    Looking ahead, the researchers will continue to explore the Khk biological pathway and to look for other promising molecular targets for treating fatty liver disease.

    "This disease is almost always associated with obesity," noted Dr. Kahn. "Once your fat cells get really full of fat and they can't hold any more, fat winds up going in other tissues, and the liver is the next best place."

    Almost all obese people with diabetes add some fat to their livers. "These people are more at risk of developing fatty liver disease, just as those with fatty liver disease are more at risk of developing diabetes, since obesity is being a predisposing factor for both conditions," commented Dr. Softic.

    As obesity spreads worldwide, so will the burden of fatty liver disease and associated liver failure, which is predicted to become the most common factor driving the need for liver transplants, he added.

    The disease afflicts people of every age, but has become a particular problem in children, now that about one-fifth of U.S. school-age children are obese, according to the Centers for Disease Control and Prevention.

    "The disease is much more worrisome in a child of thirteen who goes from normal liver to fatty liver to liver inflammation over the span of several years than in somebody who's been overweight for 30 years," stated Dr. Softic. "Kids also eat more sugar than adults, so fructose may be even more of a risk factor in children, which would add to their years of poor health."

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