鞘磷脂酰乙醇胺磷脂酶C（PE-PLC）相关的鞘磷脂合酶（SMSr）是一种在哺乳动物中广泛存在的保守分子。然而，其生物学功能仍不清楚。我们之前观察到SMS1缺陷介导的葡萄糖鞘脂醇积累引发非酒精性脂肪肝病（NAFLD），包括非酒精性脂肪性肝炎（NASH）和肝纤维化。在本研究中，首先我们评估了高脂肪饮食/果糖诱导的Smsr基因敲除（KO）和WT小鼠的NAFLD。其次，我们评估了SMSr缺陷是否能够逆转SMS1缺陷引发的NAFLD，使用Sms1/Sms2双缺陷以及Sms1/Sms2/Smsr三重缺陷小鼠模型。我们发现SMSr/PE-PLC缺陷减轻了高脂肪饮食/果糖诱导的脂肪肝和NASH，并减轻了葡萄糖鞘脂醇积累引发的NASH、纤维化和肿瘤形成。此外，我们发现SMSr/PE-PLC缺陷降低了许多炎症细胞因子和纤维化相关因子的表达，并且体外或体内的PE补充模拟了SMSr/PE-PLC缺陷的情况。此外，我们证明了SMSr/PE-PLC缺陷或PE补充有效阻止了膜结合的β-连环蛋白转移到细胞核，从而阻止了与肿瘤相关的基因表达。最后，我们观察到NASH患者肝脏中SMSr蛋白水平较高，血浆PE水平较低且血浆PE /磷脂酰胆碱（PC）比值较低，并且人类血浆PE水平与TNF-α和TGFβ1水平呈负相关。总之，SMSr/PE-PLC缺陷引起PE积累，可以减轻脂肪肝、NASH和纤维化。这些结果表明，SMSr/PE-PLC抑制剂治疗可能缓解NAFLD。版权所有 © 2023 作者，由Elsevier公司出版。保留所有权利。

Sphingomyelin synthase (SMS)-related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) molecule that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency-mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr knock out (KO) and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency-mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose-induced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PE-PLC deficiency or PE supplementation effectively prevented membrane-bound β-catenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine (PC) ratios, and that human plasma PE levels are negatively associated with TNF-α and TGFβ1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.