Figuring out the target for Lorenzo’s oil

February 7, 2014 § Leave a comment

Researchers have figured out how Lorenzo’s oil works. According to a team led by Akio Kihara and Takayuki Sassa at Hokkaido University in Japan, the mixture of oils made famous in the 1992 movie “Lorenzo’s Oil,” inhibits an enzyme that is critical for making a specific type of fatty acid chains.

Lorenzo’s oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, is used to treat a peroxisomal disorder called X-linked adrenoleukodystrophy (X-ALD). In this disease, very-long-chain saturated fatty acids don’t get degraded. They accumulate in the peroxisomes and clog them up. The defect goes on to wreck the sheath around neurons, leading to poor muscle coordination, vision loss, aggressive behavior and other symptoms. Lorenzo’s oil, with its fatty acid chains of 18 and 22 carbons, somehow normalizes the levels of saturated fatty acid chains with 24 and 26 carbons in the blood of X-ALD patients.

However, researchers have not figured out precisely how this mixture actually works at the biochemical level. In a paper just out in the Journal of Lipid Research, Kihara and colleagues demonstrated that Lorenzo’s oil targets an enzyme called ELOVL1, which makes fatty acids with more than 20 carbons.

Kihara’s group members had done a lot of work on ELOVL1 so they knew it was the main enzyme for making these very-long-chain fatty acids. “We thought it possible that Lorenzo’s oil may prevent saturated very-long-chain fatty acids from accumulating by inhibiting their synthesis through ELOVL1,” says Kihara.

The investigators already had a way to quantitatively track the activity of ELOVL1. They looked to see what effect the compounds in Lorenzo’s oil had on the enzyme. They anticipated, given ELOVL1’s role in making very-long-chain fatty acids, that Lorenzo’s oil inhibited ELOVL1. They were right. When they tested various ratios of the fatty acids in Lorenzo’s oil, oleic and erucic acids, they found the 4:1 mixture—the actual Lorenzo’s oil composition—was the most potent. The data from the various mixtures suggest that the two fatty acids in Lorenzo’s oil cooperate to inhibit ELOVL1 in places away from the substrate binding site.

At a cellular level, the investigators noted that the 4:1 mixture lowered the level of sphingomyelin made from a saturated very-long-chain fatty acid and raised the level of sphingomyelin with a monounsaturated very-long-chain fatty acid. This result may explain why Lorenzo’s oil can help reduce the risk of developing X-ALD in asymptomatic patients (who are always boys)—sphingomyelin is an important component of the sheath that goes around neurons.

Because X-ALD is caused by impaired degradation of very-long-chain fatty acids, restoring the degradation process is the obvious strategy for a treatment. But Kihara says their work suggests that stopping the very-long-chain fatty acids from being made could be an alternative. As the oleic and erucic acids bind to ELOVL1 away from the substrate binding site, Kihara says the investigators think these two oils could be lead compounds for the development of specific inhibitors of ELOVL1 that don’t affect other enzymes involved in making very-long-chain fatty acids.

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