Genome-wide liver transcriptomic profiles from chow-fed, high fat diet (HFD) fed, and HFD + AC261066 (Retinoic Acid Receptor Beta-2 Selective Agonist) fed mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE165855 | GEO | 2021/12/01
REPOSITORIES: GEO
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Project description: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/fructoseinduced 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/PEPLC deficiency or PE supplementation effectively prevented membrane-bound βcatenin 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.
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