Sphingomyelin synthase–related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease

Sphingomyelin synthase (SMS)–related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) 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 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 ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor β1 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. Sphingomyelin synthase (SMS)–related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) 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 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 ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor β1 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. The sphingomyelin synthase (SMS) gene family includes SMS1, SMS2, and SMS-related protein (SMSr) (1Huitema K. van den Dikkenberg J. Brouwers J.F. Holthuis J.C. Identification of a family of animal sphingomyelin synthases.EMBO J. 2004; 23: 33-44Crossref PubMed Scopus (497) Google Scholar, 2Tafesse F.G. Ternes P. Holthuis J.C. The multigenic sphingomyelin synthase family.J. Biol. Chem. 2006; 281: 29421-29425Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). Unlike SMS1 and SMS2, SMSr lacks SM synthase activity (1Huitema K. van den Dikkenberg J. Brouwers J.F. Holthuis J.C. Identification of a family of animal sphingomyelin synthases.EMBO J. 2004; 23: 33-44Crossref PubMed Scopus (497) Google Scholar, 2Tafesse F.G. Ternes P. Holthuis J.C. The multigenic sphingomyelin synthase family.J. Biol. Chem. 2006; 281: 29421-29425Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar), but displays ceramide phosphorylethanolamine (CPE) synthase activity in vitro (3Vacaru A.M. Tafesse F.G. Ternes P. Kondylis V. Hermansson M. Brouwers J.F. et al.Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER.J. Cell Biol. 2009; 185: 1013-1027Crossref PubMed Scopus (132) Google Scholar). However, gene KO (4Ding T. Kabir I. Li Y. Lou C. Yazdanyar A. Xu J. et al.All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity.J. Lipid Res. 2015; 56: 537-545Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 5Bickert A. Ginkel C. Kol M. vom Dorp K. Jastrow H. Degen J. et al.Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice.J. Lipid Res. 2015; 56: 821-835Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar) and overexpression (6Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866159017Google Scholar) studies were unable to confirm this activity in vivo. Thus, although SMSr is conserved throughout the animal kingdom and is expressed ubiquitously in mammalian tissues (1Huitema K. van den Dikkenberg J. Brouwers J.F. Holthuis J.C. Identification of a family of animal sphingomyelin synthases.EMBO J. 2004; 23: 33-44Crossref PubMed Scopus (497) Google Scholar, 2Tafesse F.G. Ternes P. Holthuis J.C. The multigenic sphingomyelin synthase family.J. Biol. Chem. 2006; 281: 29421-29425Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar), its biochemical activity in vivo was unknown until recently. Mammalian phospholipase C (PLC) is a group of enzymes that cleave phospholipids to produce a diacylglycerol (DAG) and a phosphorylated molecule, such as phosphorylcholine and phosphorylethanolamine (7Cheng M. Bhujwalla Z.M. Glunde K. Targeting phospholipid metabolism in cancer.Front. Oncol. 2016; 6: 266Crossref PubMed Scopus (128) Google Scholar). We and others found that SMSr has PLC activity (6Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866159017Google Scholar, 8Murakami C. Sakane F. Sphingomyelin synthase-related protein generates diacylglycerol via the hydrolysis of glycerophospholipids in the absence of ceramide.J. Biol. Chem. 2021; 296100454Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar) and specifically hydrolyzes PE, making it a phosphatidylethanolamine PLC (PE-PLC) (6Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866159017Google Scholar). We also found that SMS1 and SMS2 are two phosphatidylcholine (PC)-PLCs (9Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity.J. Biol. Chem. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). the that F. C. P. et phospholipase C in Res. PubMed Scopus Google Scholar, J. J. phospholipase C and were in to PubMed Scopus Google Scholar, Y. J. phospholipase and in the of and in 2006; PubMed Scopus (31) Google Scholar, K. H. of inhibition of phospholipase C in PubMed Scopus Google Scholar) and Mammalian phospholipase PubMed Scopus Google Scholar) and levels and many biological activity have biological PE is the phospholipid in mammalian tissues F. The of phosphatidylethanolamine and PubMed Google Scholar, The function of in the biosynthesis of Biol. Chem. Full Text PDF PubMed Google Scholar). PE in protein and and phosphatidylethanolamine in mammalian two related Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, P. The and of phosphatidylethanolamine in Biophys. PubMed Scopus Google Scholar, C. Lipid Cell Google Scholar, in to Biophys. PubMed Scopus Google Scholar). or metabolism in tissues and are to including nonalcoholic fatty liver diseases (NAFLD), and The of phosphatidylcholine and phosphatidylethanolamine metabolism in and Biophys. Acta PubMed Scopus Google Scholar, F. C. F. V. and plasma phospholipids in PubMed Scopus Google Scholar, T. et plasma and of in J. PubMed Scopus Google Scholar, F. in the of Full Text PDF PubMed Scopus Google Scholar, Li P. et metabolism homeostasis liver in PubMed Scopus Google Scholar, Y. T. et phosphatidylethanolamine are Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). its the of PE levels and the PE to diseases are of NAFLD is accumulation in the of which and Y. of accumulation in fatty liver PubMed Scopus Google Scholar). The of and in the is a fatty liver and nonalcoholic steatohepatitis (NASH) in H. M. F. The of and as and NASH in 2016; Google Scholar, J. P. Li J. et is associated with the of and the of liver in fatty liver a in PubMed Scopus Google Scholar). However, including also have in the of fatty liver and NASH J. A. in fatty liver and ceramide J. Mol. PubMed Scopus Google Scholar, M. A. H. metabolism in fatty liver PubMed Scopus Google Scholar). and two of J. Li Y. et a ceramide double and PubMed Scopus Google Scholar, H. M. J. P. J. et in 2009; PubMed Scopus Google Scholar). We that SMS1 deficiency to glucosylceramide accumulation, and this is of the the of fatty liver NASH, and and Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). SMSr is a of the we to the of SMSr/PE-PLC NAFLD. In this we that SMSr/PE-PLC deficiency attenuated or accumulation–induced NAFLD. We SMSr is a of activity and PE levels in the liver of WT had lower activity and higher PE levels in with controls and and fatty liver and NASH, we and WT with a high-fat in WT SMSr deficiency reduced the levels of plasma and The had lower levels of liver WT which was of the liver We also the with we not in we found that SMSr deficiency also reduced in the liver liver and had lower plasma activity levels in in WT we liver Smsr KO and WT and The that the absence of SMSr in the liver the expression of including and that biological were in Smsr KO including fatty and of the and is in These have or fatty liver and We in liver to gene expression levels and biological The results that fatty synthase and expression levels were reduced in in WT in gene expression levels SMSr/PE-PLC deficiency were we protein levels of and in the The results that levels of protein but not or were reduced We the of fatty liver in plasma and found that SMSr/PE-PLC of inflammatory cytokines We to specifically the levels of plasma tumor necrosis factor and two inflammatory The results that were reduced These results that SMSr/PE-PLC deficiency diet/fructose–induced fatty liver and NASH which associated with or of NASH and liver the of Google Scholar). However, we not in WT and SMSr/PE-PLC KO mice. that with and double KO with a high-fat had higher accumulation in liver that of or WT Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). Here, we Sms1/Sms2/Smsr triple KO and and and with high-fat The results that SMSr deficiency not accumulation and we the and the to the of the We levels in the liver of the and the and that were in sphingomyelin and ceramide (9Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity.J. Biol. Chem. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar) We also of PE in the liver of and and found that and were higher in in WT or and We that the had higher levels in the liver the WT Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar) C and the had lower levels in the liver the C and which to SMSr deficiency–mediated PE We the with PE and found that PE supplementation reduced glucosylceramide synthase activity These results suggest that SMSr/PE-PLC deficiency–mediated PE activity thereby levels in the observed liver in a that were a with WT and Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). The that were We in the and the with which is a K. Li T. and the to J. Mol. PubMed Scopus Google Scholar). was in WT in the and this was the We also which is the J. expression of the of human Full Text Full Text PDF PubMed Scopus Google Scholar). In liver as and We can the of is that of in WT and the liver However, the are reduced in the liver we and found that the WT and had lower that of the SMSr deficiency the liver We liver with and found that the but not WT or the had and We with and found that the had higher levels of that of WT and this was in the that SMSr deficiency reverse liver caused accumulation Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). We observed that the liver and it was to using the the were or we had the of of was that had liver of WT or the not have and were observed in not We also and in plasma and found that the had lower and activity levels that of the and We previously that the liver expressed many and such as of transforming growth factor β1 and with WT and we this to SMS1 deficiency–mediated accumulation Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). In we and and We found in with the the have and the we which are related with NASH, fibrosis, the with that of WT We and the NASH, liver fibrosis, and liver tumor of liver triple to the of PubMed Scopus Google Scholar) in the and the of expression in the that were to WT levels in the We and a and in the The levels of were in the in the that cytokines were in the plasma that in the plasma These results that SMSr deficiency NASH and caused a deficiency of SMS1 and the of PE SMSr we the with PE to triple deficiency. that the of was reduced in plasma In liver, was in the of but was reduced that PE of in the plasma mitigate liver fibrosis. We the of PE supplementation a the with with or The results that PE supplementation in reduced of growth factor and that PE supplementation liver caused We found that the but not WT and the liver and related to the A. K. C. C. P. P. et of is PubMed Scopus Google Scholar, A. Y. and in PubMed Scopus Google Scholar). in liver in β-catenin plasma the nucleus, thereby Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). We accumulation of β-catenin in the plasma of the liver and a of β-catenin in the and with the levels in the We also accumulation of in the plasma of the liver that SMSr deficiency reverse liver We the with PE to confirm results and found that PE β-catenin and liver plasma and β-catenin in the and with the levels in the that PE can and levels of We evaluated the and NASH in NASH patients and controls were with SMSr SMSr protein expression was higher in the and NASH patients a of reduced PE in the but it was not We also levels and found that the was not However, the plasma was lower in NASH patients in controls We also found that NASH patients had higher levels of plasma and and plasma levels were negatively with PE as were and PE The of with or was not and The results that plasma PE levels are negatively associated with human is the of SMSr as a we that in with WT SMSr/PE-PLC deficiency can attenuate NAFLD, including fatty liver and Second, the is a of Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar) which that the SMS1 accumulation in results in NAFLD, including fatty liver, NASH, and liver as as We found that the SMSr deficiency can reverse NASH, liver fibrosis, and tumor and that deficiency–mediated PE accumulation is the factor SMSr phosphorylethanolamine PE to ceramide in vitro to produce (3Vacaru A.M. Tafesse F.G. Ternes P. Kondylis V. Hermansson M. Brouwers J.F. et al.Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER.J. Cell Biol. 2009; 185: 1013-1027Crossref PubMed Scopus (132) Google Scholar). Smsr is expressed ubiquitously (4Ding T. Kabir I. Li Y. Lou C. Yazdanyar A. Xu J. et al.All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity.J. Lipid Res. 2015; 56: 537-545Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar), we and others that levels are in the liver and plasma (4Ding T. Kabir I. Li Y. Lou C. Yazdanyar A. Xu J. et al.All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity.J. Lipid Res. 2015; 56: 537-545Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 5Bickert A. Ginkel C. Kol M. vom Dorp K. Jastrow H. Degen J. et al.Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice.J. Lipid Res. 2015; 56: 821-835Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar) and in mammalian tissues Smsr gene KO (4Ding T. Kabir I. Li Y. Lou C. Yazdanyar A. Xu J. et al.All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity.J. Lipid Res. 2015; 56: 537-545Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 5Bickert A. Ginkel C. Kol M. vom Dorp K. Jastrow H. Degen J. et al.Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice.J. Lipid Res. 2015; 56: 821-835Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar) or overexpression (6Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866159017Google Scholar) had mammalian SMSr is not a synthase in vivo. The is of the of PE NAFLD. PE can PE levels are biosynthesis and In to a biosynthesis The function of in the biosynthesis of Biol. Chem. Full Text PDF PubMed Google Scholar), mammalian tissues have and that and to levels of and Mammalian phospholipase PubMed Scopus Google Scholar, J.F. A. of a of Res. PubMed Scopus Google Scholar, H. Y. J. Targeting phospholipase C PubMed Scopus Google Scholar). We that SMSr can PE in the absence of and SMSr expression in liver can PE levels (6Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866159017Google Scholar). We that SMSr/PE-PLC overexpression liver activity and reduced liver PE levels and SMSr/PE-PLC deficiency reduced liver activity and liver PE levels and We observed that SMSr/PE-PLC deficiency not activity that enzymes can PE to PE is and protein and is a protein and phosphatidylethanolamine in mammalian two related Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, P. The and of phosphatidylethanolamine in Biophys. PubMed Scopus Google Scholar). PE and and of and Mol. Cell Biol. PubMed Scopus Google Scholar). or metabolism in tissues and are to The of phosphatidylcholine and phosphatidylethanolamine metabolism in and Biophys. Acta PubMed Scopus Google Scholar). PE is in of the PE to diseases are We observed that SMSr/PE-PLC deficiency–mediated PE accumulation in liver attenuated high-fat diet/fructose–induced fatty liver, and that SMSr deficiency is related with and and We evaluated levels of factors, including and in NAFLD and found that SMSr deficiency can of that and inflammatory cytokines were reduced is expressed in the of K. P. Cao V. et gene expression and in the liver to Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. T. T. et in is the gene Full Text Full Text PDF PubMed Scopus Google Scholar). inhibition NASH in A. J. A. of steatohepatitis in therapy with and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). and have as a of inflammatory and is in the of many inflammatory diseases inflammatory PubMed Scopus Google Scholar), and in the and of NAFLD T. H. T. et of in the and of nonalcoholic fatty liver in a Res. PubMed Scopus Google Scholar). However, we not in WT and SMSr/PE-PLC mice. The of to with to and to of NASH and liver the of Google Scholar). The that we not in WT and the KO to the not We that the liver SM synthase and SMS2 double caused NASH, fibrosis, and liver were related to accumulation caused SMS1 deficiency Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). We that SMSr/PE-PLC deficiency reverse the observed in mice. we and observed that triple deficiency liver PE and PE with the double deficiency. We also found that the triple deficiency reduced liver levels C and and PE supplementation in vivo activity in the liver studies that inhibition in H. M. J. P. J. et in 2009; PubMed Scopus Google Scholar, M. C. M. et of metabolism and in 2009; PubMed Scopus Google Scholar, van M. J. et and Biol. PubMed Scopus Google Scholar), and is expressed in the liver of NASH patients Z. Y.P. M. H. 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The had lower levels of the of in the and lower which is associated with fibrosis, in the liver of of PE to the reduced and levels attenuated of and and which are liver The and its in liver 2016; PubMed Scopus Google Scholar). Thus, SMSr deficiency or PE effectively prevented overexpression of liver PE accumulation the fatty liver NASH and PE the of M. of phosphatidylethanolamine and of its in Biol. PubMed Scopus Google Scholar). have in in and to protein and the Lipid Res. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, I. C. The of and of Mol. Cell Biol. PubMed Scopus Google Scholar, C. of the and its Mol. Biol. PubMed Scopus Google Scholar). PE also Z. et deficiency homeostasis in and of A. PubMed Scopus Google Scholar) which is related to NASH and liver H. in liver diseases and PubMed Scopus Google Scholar). is a the of can accumulation has in a NAFLD and NASH M. in nonalcoholic PubMed Scopus Google Scholar). PE PE P. M. F. V. et and 2015; PubMed Scopus Google Scholar). of the was that SMSr deficiency prevented caused accumulation and is that a of liver can in fatty liver a PubMed Scopus Google Scholar, et and nonalcoholic PubMed Scopus Google Scholar) and is of the this A. K. C. C. P. P. et of is PubMed Scopus Google Scholar, A. Y. and in PubMed Scopus Google Scholar). can the plasma and β-catenin A. J. transforming growth to in the J. Mol. PubMed Scopus (38) Google Scholar). We previously that liver SMS1 deficiency the of which is the plasma the nucleus, to tumor gene expression Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). We found that the and the of β-catenin transfer to the C and which was observed in the Z. Y.P. M. H. Jiang X.C. sphingomyelin synthase 1 deficiency causes fibrosis, and of glucosylceramide 2021; Full Text Full Text PDF Scopus Google Scholar). Thus, SMSr deficiency or PE effectively prevented the of liver to the of liver The of therapy has The plasma of is with PE in the PE is in the in P. et a PubMed Scopus Google Scholar). and to PE and to C. K. The of 2016; PubMed Scopus Google Scholar). has that PE in tumor and P. et a PubMed Scopus Google Scholar). we that SMSr deficiency–mediated PE accumulation prevented PE related to the of β-catenin have a the of the human NASH, we to SMSr protein in the of NASH patients and We found that NASH patients had higher SMSr protein with controls and We also found that NASH patients had lower plasma PE and although the was not C and The plasma levels of two inflammatory and were higher in NASH patients with controls and and were negatively associated with plasma PE levels and However, the liver PE and NAFLD is the liver PE levels were reduced in NAFLD F. A. H. P. A. C. et a of nonalcoholic steatohepatitis in Scopus Google Scholar). the liver PE levels to the of associated NAFLD H. Y. et are associated with nonalcoholic fatty liver in and liver and J. Mol. PubMed Scopus Google Scholar). The also or can in NAFLD M. C. I. A. et and of in fatty liver PubMed Scopus Google Scholar). plasma levels PE were associated with NAFLD I. M. et phospholipids and fatty liver nonalcoholic fatty liver and 2016; PubMed Scopus Google Scholar). Thus, a of phospholipids in the the and we the plasma PE to a factor the of In we found that SMSr/PE-PLC deficiency caused PE accumulation, which can attenuate NAFLD, including fatty liver, NASH, liver fibrosis, and liver tumor that inhibition of SMSr/PE-PLC a the of NAFLD. We have (4Ding T. Kabir I. Li Y. Lou C. Yazdanyar A. Xu J. et al.All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity.J. Lipid Res. 2015; 56: 537-545Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). We with mice. we with to mice. Finally, we and with to Z. Y.P. M. K. J. et of liver sphingomyelin synthase deficiency plasma Biophys. Acta Mol. Cell Biol. Lipids. 2021; Scholar) and (6Chiang Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866159017Google Scholar, Y.P. Li Z. Chen Y. Cao Y. Jiang X.C. Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity.J. Biol. Chem. 2021; Full Text Full Text PDF PubMed Scopus Google Scholar). We and that had a were with the of the and was were with was as the the were and were with a high-fat with or in was plasma and liver were was the liver using to the was using reverse was the using the are in or were to as previously Z. Jiang H. T. Lou C. et in plasma levels of in 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). 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