Welcome to Lipids@Wayne
Lipids@Wayne is a program of Wayne State University researchers from the School of Medicine, Physics and the College of Liberal Arts and Sciences. Now in our seventh year, our twice-monthly presentations focus on cutting-edge research and technological advances in lipid research and lipidomics. These meetings have led to very fruitful collaborations.
In addition to these presentations, we sponsor an annual symposium that addresses the vital roles of lipids in cellular processes required for normal physiological function. The symposium features excellent plenary lectures from outstanding invited speakers at the cutting edge of lipid research. A poster session is also featured, which fosters discussion and sharing of research findings. Awards are given for the most outstanding posters presented by graduate students, post-doctoral fellows, and residents.
Perturbation of energy metabolism at the center of the mechanism of action of valproate
Michael Salsaa, Ph.D.
Department of Biological Sciences
Wayne State University
Bipolar disorder (BD) is a common and debilitating psychiatric disorder. Valproic acid (VPA) is one of the major drugs used to treat BD patients. However, it is not universally effective and, in addition, causes severe side effects. Its mechanism of action is not known, which complicates efforts to develop more effective drugs. Studies have established that VPA perturbs metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity.However, the mechanism whereby VPA causes these perturbations is not understood. To address this knowledge gap, I investigated the acute and chronic effects of VPA on pathways of energy metabolism utilizing the yeast model.
Chronic VPA treatment caused increased flux of [U-13C]-glucose to glycolysis, increased expression of glycolysis genes, decreased glucose-6-phosphate, and increased ethanol production. Increased glycolysis was likely a response to perturbation of mitochondrial function, as reflected in decreased membrane potential and oxygen consumption. Interestingly, yeast, mouse liver, and isolated bovine cytochrome coxidase were directly inhibited by the drug. This finding has implications for the mechanism of therapeutic action of the drug as several markers of mitochondrial activity are higher in bipolar mania than in the euthymic and depressive phases. Additionally, inhibition of mitochondrial bioenergetics has been also implicated in the mechanism of drug toxicity, as mitochondrial dysfunction is associated with microvesicular steatosis, the prominent feature of hepatotoxicity observed with VPA treatment.
In contrast to chronic VPA, acute VPA increases catabolic gene expression, which is likely mediated by activation of the Snf1 kinase. VPA activated Snf1 in the presence or absence of inositol while cytochrome coxidase (COX) inhibition did not activate Snf1, indicating that Snf1 activation by VPA is not due to inositol depletion or COX inhibition. Acute VPA increased ATP levels and mitochondrial membrane potential, and decreased glucose-induced extracellular acidification. These findings are consistent with inhibition of the P-type H+-ATPase, Pma1. In further support, omeprazole, which directly inhibits Pma1, led to Snf1 activation. These findings support a model whereby inhibition of Pma1 and the weak acid properties of VPA lead to a decrease in the intracellular pH, resulting in the acute inhibition of glycolysis. A decrease in glycolytic activity leads to the phosphorylation of Snf1 kinase, which increases catabolic gene expression.
Taken together, my studies suggest that perturbation of energy metabolism contributes to the mechanism underlying the therapeutic action of the drug. These effects include acute activation of Snf1/AMPK, acute modulation of the activity of the P-type ATPase family, chronic inhibition of mitochondrial bioenergetics, and chronic increase in glycolytic flux. In addition, as the inositol de novobiosynthesis pathway is metabolically linked to glycolysis, I hypothesize that perturbation of energy metabolism may be the mechanism of the inositol depletion effect of VPA treatment. Therefore, my studies place pathways of energy metabolism as a primary target of VPA. This knowledge may be used for the development of more effective medications with reduced toxic side effects.
How can you get involved?
We are always looking for newcomers at both our seminars and annual symposium. Those interested should check the seminar schedule and attend! We welcome all research groups from all departments, even if your primary focus is not lipids.
If you would like to be added to our e-mail list for seminar reminders and other Lipids@Wayne related information, please send an e-mail to email@example.com.