Why high-fat, low-carb diets help some epileptics

March 19, 2015 § Leave a comment

A series of pie charts depicting the calorific contributions from carbohydrate, protein and fat in four diets: the typical American diet; the Atkins diet during the induction phase; the classic ketogenic diet in a 4:1 ratio of fat to combined protein and carbohydrate (by weight); and the MCT oil ketogenic diet. Image from http://commons.wikimedia.org/wiki/File:Ketogenic_diets_pie_MCT.svg

A series of pie charts depicting the calorific contributions from carbohydrate, protein and fat in four diets: the typical American diet; the Atkins diet during the induction phase; the classic ketogenic diet in a 4:1 ratio of fat to combined protein and carbohydrate (by weight); and the MCT oil ketogenic diet. Image from http://commons.wikimedia.org/wiki/File:Ketogenic_diets_pie_MCT.svg

Antiepileptic drugs don’t work for one-third of patients. Instead, those patients usually eat ketogenic diets, high in fat and low in carbohydrates, which somehow stops seizures. In a paper just out in Science, researchers report how ketogenic diets work at the molecular level and say they designed a new drug that mimics the molecular effects of ketogenic diets.

“Current antiepileptic drugs are designed to target molecules that regulate electrical currents in neurons,” says Tsuyoshi Inoue at Okayama University in Japan, who led the work.  He adds that they “focused on antiepileptic actions of ketogenic diets” so they could find other ways to target epilepsy, particularly through metabolism.

Ketogenic diets force the body to rely on ketone bodies instead of glucose as an energy source. Inoue and colleagues explored what happens in single neurons in mouse brain slices when their energy source is switched from glucose to ketone bodies.

“We found that a metabolic pathway, known as astrocyte-neuron lactate shuttle, regulates electrical activities in neurons,” says Inoue.

An enzyme in the pathway is lactate dehydrogenase. When the energy source went from glucose to ketone bodies, the investigators realized that the switch in energy source inhibited the pathway via lactate dehydrogenase and caused the neurons to become hyperpolarized.

When the investigators inhibited lactate dehydrogenase in a mouse model of epilepsy, the animals suffered fewer seizures.

Next, the investigators used an enzymatic assay to see which existing antiepileptic drugs act on lactate dehydrogenase. They found a drug called stiripentol, used to treat a form of epilepsy called Dravet syndrome, inhibits lactate dehydrogenase. The investigators modified the drug’s chemical structure and found an analog that better suppresses seizures than the original.

Inoue says that inhibitors of lactate dehydrogenase can be “a new group of antiepileptic drugs to mimic ketogenic diets.”

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.

Unexpected role for serotonin in glucose uptake during pregnancy

November 11, 2013 § Leave a comment

Image provided by http://www.flickr.com/photos/harinaivoteza/

Image provided by http://www.flickr.com/photos/harinaivoteza/

Pregnancy demands a lot from the mother’s metabolism: She has to steadily supply sufficient amounts of nutrients to the growing fetus over the course of 40 weeks. One of these nutrients is glucose. Insulin-secreting beta cells in the mom’s pancreas adapt to make sure the fetus gets enough glucose throughout pregnancy. In a paper just out in the Proceedings of the National Academy of Sciences, researchers describe a mechanism that they’ve discovered that adjusts the size and insulin secretory capacity of the beta-cell population to keep up with the metabolic demands of pregnancy.

Early in pregnancy, a mother grows more insulin-secreting beta cells in her pancreas. Insulin helps the body’s various organs take up glucose. Defects in insulin regulation can lead to gestational diabetes in pregnant women.

A group of researchers led by Michael German at the University of California, San Francisco, had earlier reported that pancreatic islets, which contain the beta cells, in pregnant mice and women expressed large amounts of two enzymes involved in the synthesis of the neurotransmitter serotonin. These cells also secreted high amounts of serotonin.  “We suspected that these high local levels of serotonin acted locally,” says German.

The group demonstrated that serotonin helped beta cells to proliferate. But how did serotonin tie into insulin secretion?

In this PNAS paper, German, Shinya Nagamatsu at the Kyorin University School of Medicine in Japan, and colleagues demonstrated that a receptor on beta cells, called the ionotropic Htr3 serotonin receptor, is stimulated by serotonin. This action of serotonin on the receptor makes beta cells secrete insulin sooner than normal during pregnancy. German says, “We did not know how important serotonin signaling was for insulin secretion during pregnancy.”

This finding can impact several areas, including the use of some medications during pregnancy. “Many drugs affect the serotonin system,” says German. “These studies also could have applications to non-gestational diabetes.  Understanding how serotonin affects beta-cell proliferation and secretion could lead to methods for replacing the beta-cells that are destroyed in type 1 diabetes, or for increasing the beta-cell mass and secretory capacity in type 2 diabetes.”

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