Abstract
During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury.
Highlights
During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver
On day 3, necrotic hepatocytes were prevalent around the central vein along with inflammatory infiltration, and the development of microvesicular steatosis was evident in the surrounding cells (Fig. 1A and supplementary Fig. I-A)
Consistent with the histological observation, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity remained unchanged on day 1 but dramatically increased on day 2 and 3 of cocaine treatment (Fig. 1B and supplementary Fig. I-B), which suggests that cocaine-induced damage on hepatocytes at this dose (30 mg/kg) is a subacute toxic event instead of an acute one
Summary
During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. To further explore the metabolic events associated with subacute hepatotoxic effects of cocaine, especially the changes in the lipidome, serum samples and liver lipid extracts were examined through LC-MS-based lipidomic analysis.
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