Abstract 236: Impact On Smsr, As A Pe-plc, On Nash And Liver Fibrosis

Sphingomyelin synthase-related protein (SMSr), a member in SMS gene family, has no SM synthase activity. Although SMSr is conserved throughout the animal kingdom and ubiquitously expressed in all tested mammalian tissues, its biochemical activity in vivo is unknown till very recently. We found that SMSr is a phosphatidylethanolamine-specific phospholipase C (PE-PLC) which is involved in tissue PE steady-state regulation. We also found that Sms1/Sms2 double knockout (KO)-mediated glucosylceramide accumulation caused liver impairment, inflammation, and fibrosis. Importantly, these pathologic phenotypes could be reversed, at least partially, in Sms1/Sms2/Smsr triple KO mouse livers. Based on RNA-seq, we noticed that about 60 pro-inflammatory and fibrosis genes, including TGFb1, TNFa, IL-1a, IL-6, and collagen 1a1, were significantly upregulated in Sms1/2 double KO mouse liver compared with wild type mouse liver, while the triple KO mice could reduce them. The observations were confirmed by real-time PCRs. Further, we found that Sms1/Sms2/Smsr triple KO mice had much less liver PE-PLC activity and higher PE levels compared with the double KO mice. We also measured plasma TGFb1 whose signaling in hepatocytes participated in NASH and liver fibrosis and found the triple KO mice had significantly lower active TGFβ1 in the circulation compared with the double KO mice. Moreover, we treated the double KO mice with PE (i.p.) (10 mg/kg) every day for 7 days to mimic the situation of SMSr deficiency and we found that the active form of TGFβ1 in the plasma was also dramatically reduced in PE-treated mice compared with vehicle. These findings implicated SMSr/PE-PLC deficiency-mediated PE accumulation can prevent the development of NASH and liver fibrosis. Thus, SMSr could be drug target for the treatment of both.