Date of Award

January 2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Thad A. Rosenberger

Abstract

Acetate supplementation is anti-inflammatory and neuroprotective in rat models of neuroinflammation and Lyme neuroborreliosis. Oral administration of glyceryl triacetate (GTA) is used to induce acetate supplementation in rodents, which increases plasma acetate and brain acetyl-CoA levels. Acetyl-CoA is a ubiquitous substrate for several biochemical pathways including carbohydrate, protein, and lipid metabolism. Acetate increases the in vivo and in vitro acetylation-state of histones and is associated with altered cytokine balance. However, the effect that acetate supplementation has on brain purine and lipid content remains unknown. Since labeled-acetate is incorporated into the purine and lipid pools, we proposed that acetate supplementation by increasing acetyl-CoA levels stimulates purine and lipid metabolism which in turn reduce inflammation and increase lipid deposition. To begin to test this hypothesis, we measured the effect of single-dose GTA on brain purine levels and demonstrated that it not only increases brain energy reserves but can potentially alter brain purine metabolism. Consequently, we used different treatment regimens to test GTA's potential in altering purinergic enzymes and receptors in a rat model of neuroinflammation. Both prophylactic and interventional acetate supplementation modulate LPS-induced alterations in the activity and levels of adenosine metabolism enzymes and receptors. To further determine the mechanism(s) by which acetate alters purine metabolism and inflammation, we used in vitro BV2 microglia and primary astrocyte cell cultures. These experiments showed that in vitro acetate treatment had distinct cell-type specific effects on LPS-induced changes in adenosine metabolizing enzyme and receptor levels. These data suggest that GTA could be used to modulate inflammation by altering the endogenous response to adenosine and adenine nucleotides. Lastly, studies testing the concentration-dependent effects of acetate on fatty acid, phospholipid, and cholesterol content showed that lower acetate concentrations increase fatty acid and cholesterol levels in BV2 cells. This proof-of-principle experiment suggests that acetate may be utilized for stimulating lipid synthesis and concentration-dependent therapeutic strategies can be developed to selectively target disorders requiring either enhanced lipid synthesis, or attenuation of inflammation. Overall these data suggest that acetate increases brain purine metabolism and glial fatty acid content which may contribute to its anti-inflammatory properties and potentially stimulate lipid deposition.

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