Completed Studies

Study 1: Pharmacometabolomics of statins in the treatment of hyperlipidemia.

Over the last three years, the network has explored approaches for mapping pathways implicated in variation in response to statins. Statins are HMG CoA reductase inhibitors that lower lipids and that are used to treat cardiovascular disease (CVD), a disease that is the leading cause of death in the United States. Statins reduce blood LDL-cholesterol levels by inhibiting HMG CoA reductase, and they are the largest single class of drugs prescribed for CVD prevention. CVD risks are due in large part to in­creased LDL and IDL clearance as a result of the upregulation of LDL receptors. Multiple intervention trials with statin drugs have demonstrated a remarkable consistency in their ability to reduce risk for both CVD and stroke by an average of approximately 1/4 to 1/3. Nevertheless, in all of these trials, residual CVD risk remains high (60-75%). Potential drug-related toxicity, while infrequent, is a significant concern with a large individual variation in drug response after statin therapy. Patients receiving statins have lower event rates than that predicted by their achieved LDL-C, raising the possibility of distinct mechanisms beyond cholesterol reduction (cholesterol-independent effects).

The biochemical basis for variation in response remains poorly understood. Through partnership with Dr. Krauss, we initiated pilot studies to evaluate potential of metabolomics and lipidomics in defining pathways implicated in variation in response to simvastatin. Profiling close to 200 samples from his Cholesterol and Pharmacogenetics (CAP) simvastatin pharmacogenomics study we were able to derive new insights and highlight pathways that correlate with changes in LDC cholesterol or with CRP.

Data from fatty acid content and composition revealed that differences in lipid metabolites occurred in multiple lipid classes including cholesterol esters, phospholipids and triglycerides upon simvastatin treatment. Different pathways and enzymes possibly implicated in variation in response were highlighted. Additionally we evaluated which lipids correlate with changes in CRP, another marker for cardiovascular health, and compared metabolic signatures that correlate with LDLC to those that correlate with CRP. Baseline levels of cholesterol esters and phospholipids correlated with LDL-C response to treatment. CRP response to therapy correlated with baseline plasmalogens, lipids involved in inflammation. There was no overlap in the lipids whose changes correlated with LDL-C or CRP responses to simvastatin distinct metabolic pathways govern these two biomarkers.

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Study 2: Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions.

In a project led by Teresa Fan, Andrew Lane and Richard Higashi and in collaboration with the PI at Duke and NIMH collaborators we explored the power of stable isotope resolved metabolomics in helping us understand basic biochemical communication between astrocytes and neurons and for mapping effect of CNS drugs on this biochemical communication.

The effect of lithium on the metabolism of three different 13C-labeled precursors ([U-13C]-glucose, 13C-3-lactate or 13C-2,3-alanine) was analyzed in cultured rat astrocytes and neurons by nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GC-MS). Using [U-13C]-glucose, lithium was shown to enhance glycolytic activity and part of the Krebs cycle activity in both astrocytes and neurons, particularly the anaplerotic pyruvate carboxylation (PC). The PC pathway was previously thought to be active in astrocytes but absent in neurons. Lithium also stimulated the extracellular release of 13C labeled-lactate, -alanine (Ala), -citrate, and –glutamine (Gln) by astrocytes. Interrogation of neuronal pathways using 13C-3-lactate or 13C-2,3-Ala as tracers indicated a high capacity of neurons to utilize lactate and Ala in the Krebs cycle, particularly in the production of labeled Asp and Glu via PC and normal cycle activity. Prolonged lithium treatment enhanced lactate metabolism via PC but inhibited lactate oxidation via the normal Krebs cycle in neurons. Such lithium modulation of glycolytic, PC and Krebs cycle activity in astrocytes and neurons as well as release of fuel substrates by astrocytes should help replenish Krebs cycle substrates for Glu synthesis while meeting neuronal demands for energy. Further investigations into the molecular regulation of these metabolic traits should provide new insights into the pathophysiology of mood disorders and early diagnostic markers, as well asnew target(s) for effective therapies.

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