Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Abstract

ObjectiveLipotoxic 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 pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.DesignWild-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).ResultsHFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented 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, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.ConclusionSMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

“…Mechanistically, it is unclear how GSDMD is activated by hyperglycaemia in macrophages. A recent study revealed the leading role of NLRC4‐dependent pyroptosis in steatohepatitis (Koh et al, 2020). Following our previous findings that NLRC4 phosphorylation plays an important role in hyperglycaemia (P. Zhang, Wang, et al, 2019), we investigated the role of NLRC4 in pyroptotic cell death.…”

“…A previous study revealed that NLRC4 is responsible for IL‐1β production and macrophage infiltration in diabetic nephropathy (F. Yuan et al, 2016). In addition, NLRC4‐dependent pyroptosis, but not NLRP3, plays a significant role in steatohepatitis (Koh et al, 2020). Therefore, in this study, we assessed NLRC4 in hyperglycaemia‐induced pyroptosis.…”

Pyroptosis, metabolism, and tumor immune microenvironment

“… 210 Sphingomyelin synthases (SMSs) could generate sphingomyelin (SM) and diacylglycerol (DAG), while free cholesterol and SMSs in hepatocytes are found to mediate hepatocyte pyroptotic injury through DAG‐PKCδ‐NLRC4 axis. 211 It has been reported that geranylgeranoic acid (GGA) (C20:4) could induce pyroptotic cell death in human hepatoma‐derived HuH‐7 via toll‐like receptor 4 (TLR4) signaling pathway. In fact, GGA is a branched‐chain polyunsaturated fatty acid, an endogenous metabolite derived from the mevalonate pathway in mammals.…”

“…A possible explanation is that PA‐related pyroptosis may contribute to endoplasmic reticulum (ER) stress in HepG2 cells, and OA is capable of improving hepatocellular lipotoxicity both in vitro and in vivo 210 . Sphingomyelin synthases (SMSs) could generate sphingomyelin (SM) and diacylglycerol (DAG), while free cholesterol and SMSs in hepatocytes are found to mediate hepatocyte pyroptotic injury through DAG‐PKCδ‐NLRC4 axis 211 . It has been reported that geranylgeranoic acid (GGA) (C20:4) could induce pyroptotic cell death in human hepatoma‐derived HuH‐7 via toll‐like receptor 4 (TLR4) signaling pathway.…”

DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs

“…In response to potassium efflux, the NIMA (never in mitosis, gene A) related kinase 7 acts as an essential partner that interacts with NLRP3 and licenses its activation (20,21). In addition, cross-talk between NLRP3 and NLRC4 was revealed by studies in Escherichia coli-and Salmonella typhimurium-induced inflammation (22)(23)(24) and in sterile inflammation induced by lysophosphatidylcholine (LPC), hyperosmotic stress, or diacylglycerol (DAG) (25)(26)(27)(28). During S. typhimurium infection, NLRP3 and NLRC4 can be recruited to same macromolecular complex through ASC (29,30).…”