Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation.

ABSTRACT: Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate

SUBMITTER: Li Z 

PROVIDER: S-EPMC8649732 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature