Disturbing Cholesterol/Sphingolipid Metabolism by Squalene Epoxidase Arises Crizotinib Hepatotoxicity.

Abstract

Metabolic disorders have been identified as one of the causes of drug-induced liver injury; however, the direct regulatory mechanism regarding this disorder has not yet been clarified. In this study, a single regulatory mechanism of small molecule kinase inhibitors, with crizotinib as the representative drug is elucidated. First, it is discovered that crizotinib induced aberrant lipid metabolism and apoptosis in the liver. A mechanistic study revealed that crizotinib treatment promoted the accumulation of squalene epoxidase (SQLE) by inhibiting autophagosome-lysosome fusion which blocked the autophagic degradation of SQLE. A maladaptive increase in SQLE led to disturbances in cholesterol and sphingolipid metabolism via an enzymatic activity-dependent manner. Abnormal cholesterol results in both steatosis and inflammatory infiltration, and disturbances in sphingolipid metabolism promote cell apoptosis by inducing lysosomal membrane permeabilization. The restoration of the level or activity of SQLE ameliorated steatosis and hepatocyte injury. The autophagy activator known as metformin or the SQLE enzymatic inhibitor known as terbinafine has potential clinical use for alleviating crizotinib hepatotoxicity.