High fat and high cholesterol diet significantly increased hepatic levels of sphingomyelin (SM) and diacylglycerol (DAG) in mouse models of non-alcoholic steatohepatitis (NASH).
Increased hepatic sphingomyelin and diacylglycerol levels are associated with the development of NASH.
Free cholesterol in hepatocytes stimulates the expression of sphingomyelin synthases (SMSs).
Knockdown of SMS1 or protein kinase Cδ (PKCδ) may prevent NASH development and hepatocyte .
DAG produced by SMS1 activates PKCδ and the , leading to programmed cell death in hepatocytes.
Conditioned media from pyroptotic hepatocytes can activate the NLRP3 inflammasome in Kupffer cells, indicating intercellular signaling.
Simplified
OBJECTIVE: Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte , a specific form of programmed cell death associated with inflammasome activation, and NASH.
DESIGN: Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).
RESULTS: HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression ofbut notwas higher in mouse models and patients with NASH. FC in hepatocytes inducedexpression, andknockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and to induce hepatocyte pyroptosis. Depletion ofprevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, butknockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. Sms1Sms2Sms1Sms1Nlrc4Nlrp3
CONCLUSION: SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.
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