Metabolomics‐based investigation of cocaine‐induced disruption of lipid metabolism

Abstract

Besides its psychological and behavioral effects, cocaine can also cause liver injury. Lipid accumulation in the liver is a pathological change occurred prior to cell death. However, the specific effects of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, we conduct metabolomic analysis of serum samples from control and cocaine‐treated mice, along with histological and biochemical analyses. During 3‐day cocaine injection, hepatocytes in pericentral vein zone underwent progressive impairment. Serum transaminase activity was elevated dramatically at the 2nd day of cocaine treatment while the increase of both serum and hepatic triglyceride levels occurred at the 1st day of cocaine injection, suggesting the disruption of lipid metabolism preceded cell death in cocaine‐induced hepatotoxicity. LC‐MS‐based metabolomic analysis revealed that the accumulation of long‐chain acylcarnitines in serum, together with the imbalance between phosphotidylethanolamine and phosphatidylcholine species, contributes to the time‐dependent separation of control and cocaine‐treated mice in a multivariate model. Pretreatment of fenofibrate, an agonist of transcriptional factor PPARα that regulate fatty acid oxidation, completely reversed the increases of acylcarnitine level and transaminase activity and abolished cocaine‐induced cell death, suggesting that the inhibition of fatty acid oxidation plays an important role in the cocaine‐induced liver injury. Overall, our metabolomic investigation detected the unreported metabolic events elicited by cocaine exposure and provided novel insights on the underlying mechanism of these events.Grant Funding Source : NIH