Fatty acid made in the lab can tame inflammation

It is a hotly debated, highly researched subject: which fats are good for us and which aren’t?

Many scientists have assumed that oxidized fatty acids cause and promote inflammation. An example is the low-density lipoprotein (LDL), a delivery vehicle for cholesterol and fatty acids that every cell needs and takes from the blood. Excessive amounts of LDL are thought to cause atherosclerosis.

“This substance has a very high potential for use against various inflammatory diseases, such as psoriasis and colitis, or even autoimmune diseases, such as multiple sclerosis.”

This is an inflammatory process in which foam macrophages (scavenger cells) that incorporate too much LDL or other lipids are deposited on artery walls and form plaque. If the plaque is released into the bloodstream, it can become stuck in the small blood vessels, causing a stroke or heart attack.

LDL is regarded as a “bad cholesterol” in contrast to high-density lipoprotein (HDL), the “good cholesterol,” and is considered particularly dangerous when the fatty acids in LDL are oxidized.

Manfred Kopf, a professor at ETH Zurich, and his team looked at the general question of how fatty acids influence inflammatory processes in the body. They were particularly interested in the role played by oxidized lipids.

When the team put scavenger cells (macrophages) in a cell culture and fed them both LDL and the oxidized form, they got an unexpected result: the oxidized LDL inhibited the secretion of pro-inflammatory signal substances in the macrophages, which suppressed the inflammation.

“This finding was surprising. It was contrary to the conventional school of thought and was difficult to publish, especially as some publications had come to the conclusion that oxidized fatty acids promote inflammation,” recalls Kopf.

Their results led them to a different conclusion: “When fatty acids are burned, different oxidization products form, which inhibit some inflammation.”

Potent anti-inflammatory

The researchers, in collaboration with Professor Köfeler’s group at the University of Graz, discovered that dozens of different types of oxidation products are formed when fatty acids are oxidized. Their composition depends on the duration of oxidation and the oxidizing agent.

Erick Carreira, a chemistry professor at Zurich, and his group ultimately succeeded in recreating some of these lipids in the laboratory, among them two epoxyisoprostanes (EI and EC).

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In terms of their chemical structure, these are very similar to prostaglandins, which are formed in the body through spontaneous oxidation of arachidonic acid—found in animal fat, for example. But unlike the pro-inflammation prostaglandins E2 and A2, the researchers found that the two epoxyisoprostanes EI and EC were anti-inflammatory.

Carreira and his team also found new synthetic pathways to change EC chemically. One variant, which the researchers named cyclo-EC, seems to be a particularly potent anti-inflammatory, with an efficacy 50 times higher than that of a known endogenous EC-like lipid.

Treat inflammatory diseases?

Through experiments on mice, the researchers were able to show that EC and cyclo-EC could mitigate the effects of bacterial pneumonia. They also discovered how the anti-inflammatory effect in macrophages comes about.

Kopf and Carreira have now patented the substance cyclo-EC and its synthesis route.

“This substance has a very high potential for use against various inflammatory diseases, such as psoriasis and colitis, or even autoimmune diseases, such as multiple sclerosis,” says Kopf. “The patent could help make pharmaceutical companies aware of this drug class.”

The researcher hopes that he can persuade a company to drive further development.

“Currently, there is still no pharmacokinetic study, which is why companies are hesitant to address it,” he admits. Such studies will seek to clarify how a drug spreads through the body and how quickly it degrades.

Source: ETH Zurich

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Source: Futurity