ETH researchers find a previously unknown fructose-dependent molecular mechanism that may contribute to heart enlargement and failure.

Fructose causes heart muscle cells to grow faster and without negative feedback. (Montage: Peter Mirtschnik / ETH Zurich)
"Take a walk through a supermarket and look at the food labels - many of them also contain fructose in the form of sucrose, i.e. household sugar," says Wilhelm Krek, Professor of Cell Biology at the Institute of Molecular Health Sciences at ETH Zurich, summing up the problem with today's foods. Ready-made products, soft drinks in particular, but also supposedly healthy fruit juices contain artificially added fructose - often in huge quantities.

Fructose has conquered the food market in recent decades because it was considered less harmful than glucose. In contrast to glucose, fructose hardly causes any insulin release and the glucose level in the blood rises only slightly. The insulin spikes that are considered harmful and recur with every intake of glucose-containing food can thus be avoided. In addition, people perceive fructose as having a much sweeter taste.

The disadvantage: the liver converts fructose very efficiently into fat. Over time, people who consume excessive amounts of foods with a high fructose content can suffer from obesity, high blood pressure, lipometabolic disorders with fatty liver and insulin resistance, a clinical picture that doctors summarize under the term metabolic syndrome.

Unchecked heart muscle growth
In a new publication, Wilhelm Krek and his research assistant Peter Mirtschink have now revealed another controversial "side effect" of fructose. The researchers have discovered a previously unknown molecular mechanism that identifies fructose as a key driver of uncontrolled growth of the heart muscle, which can even lead to fatal heart failure. The study has just been published in Nature.

If a person suffers from high blood pressure, the heart has to grow in order to pump more blood into the circulatory system. However, the growing heart muscle cells need a lot of oxygen. However, as this cannot be provided in sufficient quantities during the increased growth, the cells switch their energy production. Instead of obtaining energy from fatty acids, they increasingly use glycolysis, i.e. the oxygen-free breakdown of sugars. If fructose is available to the heart muscle cells in addition to glucose, a fatal chain reaction is set in motion.

Switch for fructose metabolism flipped
In their study, Krek's research group shows that the lack of oxygen in the heart cells triggers the HIF molecule. This is a universal molecular switch that always comes into action in pathological growth processes, be it heart enlargement or cancer. In the heart muscle cells, it ensures that the central enzyme of the fructose metabolism, ketohexokinase-C (KHK-C), is formed. KHK-C has a high affinity for fructose and can therefore process it very efficiently. The formation of KHK-C also has an enhancing effect on glycolysis. As the metabolism of fructose has no negative feedback, a vicious circle begins that can lead to heart failure.

The researchers tested this mechanism not only on mouse models, but also on biological samples from patients. These patients suffered from pathological heart enlargement with a corresponding narrowing of the heart valve to the aorta. During operations on the heart, surgeons were able to obtain samples of heart muscle cells in which the ETH researchers were actually able to detect more HIF and CHD-C molecules. In mice suffering from chronic high blood pressure, the researchers switched off the CHD enzyme. This actually prevented the heart from enlarging.

One gene, two enzymes
Another remarkable fact is that there is a very similar variant of KHK-C in the body, the enzyme KHK-A, which has no preference for fructose. However, both enzymes have the same genetic code. What is important is that the blueprint for the two enzymes, i.e. the messenger RNA, which is a copy of the corresponding gene, is cut in different ways as required by a molecular cutting tool. In this way, two blueprints and consequently two different enzymes can be generated from one gene. Experts call this process "alternative splicing". "Around 95 percent of all human genes are alternatively spliced," says Krek, "this is the only way that the extraordinary diversity of proteins, enzymes and regulators in the human body can be formed at all."

Normally, only liver cells produce the fructose-affine CHD-C enzyme. The other organs almost exclusively produce KHK-A. The ETH researchers have now shown for the first time that an organ such as the heart is also capable of producing the more efficient of the two enzymes when it is exposed to pathological stressors. HIF activates the molecular cutting tool SF3B1. Interestingly, SF3B1 is often genetically altered in many types of cancer, possibly suggesting that the growth of cancer could also be influenced by fructose.

Normal fruit consumption is harmless
Fructose is added in large quantities in many foods, but especially in sweet drinks and soft drinks. In the USA, the consumption of high-fructose corn syrup rose from 230 grams per person per year to over 28 kilograms between 1970 and 1997.

According to Peter Mirtschink, however, eating a normal daily ration of fruit is safe and healthy. "In addition to fructose, fruit also contains numerous important trace elements, vitamins and fiber," he says. However, you should avoid highly sweetened soft drinks and fruit juices - these are often sweetened - and ready meals and other dishes that use large amounts of fructose as a flavor carrier. "This surplus of fructose can already contribute to triggering the mechanism we have described if one of the stress factors such as heart valve disease or high blood pressure is present," emphasizes Mirtschink.