Could the Keto Diet Control Seizures?
Background
If you’ve ever seen someone have a seizure or experienced one yourself, you know it can be kind of scary when it happens, especially if you don’t know what’s going on. This article looks at seizures and tries to figure out what’s involved. The researchers end up studying the effect that ketogenesis can have on seizures. More specifically, they take a look at the role of the protein, zinc-α2-glycoprotein (ZAG), in the regulation of ketogenesis itself. Ketogenesis is the biochemical process that an organism uses to break down fatty acids and some amino acids. The breakdown results in an alternate source of energy from glucose: ketone bodies. These molecules are produced by the liver and contain a (you guessed it) ketone group. Normally, ketogenesis occurs in states of low fuel intake ranging from decreased food consumption and low carbohydrate diets to true starvation. To learn more about ketogenesis, check out this review. Ketone bodies are known to suppress seizures, but this study looks at what factors regulate ketogenesis in epilepsy and whether ketone body deficiency exists in seizure patients. ZAG has many functions, but its role in metabolism as a lipid-organizing factor is explored in this paper. Basically, it stimulates both lipid and glucose breakdown which are huge players in the body’s overall metabolism. The researchers connected ZAG specifically to epilepsy and found it localized in both human and rat neurons during the study. Several other proteins important to this research are L-3-hydroxyacyl-CoA dehydrogenase (HADHB), heat shock cognate protein 70 (HSC70), and peroxisome proliferator-activated receptor γ (PPARγ). HADHB is a mitochondrial protein that ZAG binds to promote ketogenesis. HSC70 is a chaperone molecule in the mitochondria that enables translocation of various proteins into the organelle, and PPARγ is a transcription factor that binds to the promoter region of the ZAG gene (AZGP1). The experimental data showed several connections between all these proteins.
Summary: ZAG & Co.
In the study, researchers found interactions between ZAG, HSC70, HADHB, and PPARγ. Data determined that ZAG is one of the proteins HSC70 shuttles into the mitochondria. Their experiments also detected interactions between ZAG and HADHB. ZAG binds to the four β-subunits of HADHB, which facilitates β-oxidation of fatty acids in the mitochondria (aka ketogenesis). Chromatin immunoprecipitation(ChIP) established that suppression of PPARγ resulted in a decrease in ZAG expression while activation of PPARγ showed an upregulation of ZAG. This makes sense since PPARγ binds to the promoter region of AZGP1, so preventing it from binding would result in decreased expression. Tying this together, ZAG, a necessary protein for stimulation of fatty acid β-oxidation, needs to get into the mitochondria to begin that oxidation process. But it can’t get itself across the mitochondrial membrane into the matrix, which is where HSC70 comes in. It acts as a shuttle for ZAG and brings it across the membrane. Once in the mitochondria, ZAG interacts with HADHB by binding to four β-subunits of its long chain form. That contact begins ketogenesis while PPARγ, when bound, enhances ZAG expression, promoting more transport into the mitochondria. Researchers used differing combinations of control and PTZ-kindled rats (chemical injections that induce acute seizing) as well as various neuron cultures to test the influences of each of these proteins on each other and how they affect neuronal ketogenesis.
The purpose of the study was to see how ketogenesis influences seizures. To do this, they targeted a specific protein, ZAG, and looked at several factors that influence ZAG to determine how it all works together in neuronal ketogenesis. Previous studies indicated that ketone bodies suppress seizures, but the researchers didn’t know exactly how. By the end of their experimentation, they discovered that ZAG, along with its regulators and “helper” proteins, showed decreased expression in seizure models, while overexpression of ZAG lessened both the severity and frequency of seizures. So could getting on the keto diet possibly help control seizures? Maybe so — after all, the keto diet promotes elevated ketogenesis which seems to require higher levels of ZAG. All this data from the research, then, could help the development of future seizure-specific treatments. Since elevated expression of ZAG suppresses seizures, targeting it could be a critical step in better controlling epilepsy.
