Hepatocyte Lethal and Nonlethal Lipotoxic Injury

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Hepatocyte injury caused by accumulation of excess lipid intermediates, known as hepatocyte lipotoxicity, is intricately linked to the pathogenesis of obesity-associated nonalcoholic steatohepatitis (NASH). Although both hepatocyte cell injury and inflammation occur in this disease process, the cellular and molecular mechanisms linking hepatocyte injury to inflammation remain unclear. Although multiple cell types contribute to hepatic inflammation in NASH, the predominant cell types appear to be macrophages. In this review, we discuss lipid-induced apoptosis and sublethal signaling events described in lipid-loaded hepatocytes, and how they promote macrophage-associated inflammation. The saturated free fatty acid palmitate and its derivative lysophosphatidylcholine activate cellular apoptotic pathways by upregulating the proapoptotic proteins, including BH3-only protein PUMA and the death receptor TRAIL-R2, which cooperatively promote lipoapoptosis. Hepatocyte apoptosis may contribute to hepatic inflammation and fibrosis via generation of apoptotic bodies. These apoptotic bodies are engulfed by macrophages and stellate cells promoting liver inflammation and fibrosis, respectively. However, recent studies also suggest that proapoptotic, but nonlethal, signaling in hepatocytes leads to the release of extracellular vesicles, which promote hepatic inflammation by inducing macrophage chemotaxis and activation. The vesicle cargo promoting these macrophage processes includes CXCL10, TRAIL, and sphingosine 1-phosphate. Thus, we discuss the possible relative contributions of both hepatocyte apoptotic cell death and nonlethal proapoptotic signaling in generating macrophage-driven hepatic inflammation during NASH.