Johns Hopkins researchers have discovered that valproic acid, a widely prescribed drug for treating epilepsy, has the additional benefits of reducing fat accumulation in the liver and lowering blood sugar levels in the blood of obese mice. A summary of their research appears in this month’s issue of the journal Molecular Pharmacology.
The liver cells (magenta) of untreated obese mice (left) contain many large, white droplets of fat while those of obese mice treated with valproic acid (right) have much less fat accumulation.
Used with permission of Molecular Pharmacology and Namandje Bumpus.
Fatty liver disease can lead to liver failure and is often caused by obesity and a high-fat diet. Obesity is also associated with the development of type 2 diabetes, which sabotages the body’s process for controlling blood sugar levels. A rapidly rising problem in the developed world, obesity currently affects over 90 million Americans.
Studying the ways in which the cytochrome P450 family of enzymes processes valproic acid, the Johns Hopkins biochemists found that it can activate the protein AMPK, which was already known to be a good drug target for treating metabolic disorders like type 2 diabetes and obesity.
The Bumpus laboratory studies how drugs are processed in cells by enzymes of the cytochrome P450 family. Humans have 57 of these enzymes, and several of them work on the drug valproic acid. In the course of their research, Namandjé Bumpus, Ph.D., assistant professor of pharmacology, and postdoctoral fellow Lindsay Avery, Ph.D., found that valproic acid could activate AMPK in mouse and human liver cells in a dose-dependent way.
“It was exciting to find that valproic acid can activate AMPK,” Bumpus says. “What’s even better is that its byproducts can activate AMPK at much lower doses. That’s a desirable quality if you want to eventually use it to treat people.”
Knowing that valproic acid is extensively processed by cytochrome P450 enzymes, the research team added a cytochrome P450 inhibitor to mouse and human liver cells and found that AMPK was no longer activated. This suggested that the byproducts of valproic acid, as opposed to valproic acid itself, were the molecules activating AMPK. To test this theory, they added four chemically modified versions of the drug to the cells and found that the derivatives were able to activate AMPK without valproic acid. In fact, they achieved higher activation of AMPK at one-fortieth the concentration.
To assess the uptake and breakdown of valproic acid in living organisms, they gave the drug to obese mice with high blood sugar levels, fatty livers and rapid weight gain. Treated mice showed decreased blood sugar levels, decreases in the size and the fat accumulation of their livers, and a stabilization of weight — rather than the continued weight gain experienced by untreated mice.
“The improvements seen in the health of these obese mice were very encouraging,” says Bumpus. “We hope that we will find similar results in obese people who take valproic acid.”
This work was supported by a grant from the National Institute of General Medical Sciences (R01GM103853).
Catherine Kolf | EurekAlert!
A study shows how the brain switches into memory mode
06.05.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn
An experimental Alzheimer's drug reverses genetic changes thought to spur the disease
04.05.2016 | Rockefeller University
Using an ultra fast-scanning atomic force microscope, a team of researchers from the University of Basel has filmed “living” nuclear pore complexes at work for the first time. Nuclear pores are molecular machines that control the traffic entering or exiting the cell nucleus. In their article published in Nature Nanotechnology, the researchers explain how the passage of unwanted molecules is prevented by rapidly moving molecular “tentacles” inside the pore.
Using high-speed AFM, Roderick Lim, Argovia Professor at the Biozentrum and the Swiss Nanoscience Institute of the University of Basel, has not only directly...
If a person pushes a broken-down car alone, there is a certain effect. If another person helps, the result is the sum of their efforts. If two micro-particles are pushing another microparticle, however, the resulting effect may not necessarily be the sum their efforts. A recent study published in Nature Communications, measured this odd effect that scientists call “many body.”
In the microscopic world, where the modern miniaturized machines at the new frontiers of technology operate, as long as we are in the presence of two...
Researchers from the Max Planck Institute Stuttgart have developed self-propelled tiny ‘microbots’ that can remove lead or organic pollution from contaminated water.
Working with colleagues in Barcelona and Singapore, Samuel Sánchez’s group used graphene oxide to make their microscale motors, which are able to adsorb lead...
Neutron scattering and computational modeling have revealed unique and unexpected behavior of water molecules under extreme confinement that is unmatched by any known gas, liquid or solid states.
In a paper published in Physical Review Letters, researchers at the Department of Energy's Oak Ridge National Laboratory describe a new tunneling state of...
Honeycomb structures as the basic building block for industrial applications presented using holo pyramid
Researchers of the Alfred Wegener Institute (AWI) will introduce their latest developments in the field of bionic lightweight design at Hannover Messe from 25...
27.04.2016 | Event News
15.04.2016 | Event News
12.04.2016 | Event News
06.05.2016 | Earth Sciences
06.05.2016 | Life Sciences
06.05.2016 | Life Sciences