FIG. 1.

Germline deletion of neutral ceramidase (Asah2 ^–/–) mice mitigates inflammation and fibrosis in diet-induced NASH. The key pathways include impaired intestinal sphingolipid degradation and increased sIgA production with altered microbial taxa. Systemic (unknown) signals as well as microbial-derived products reduce up-regulation of hepatic SCD1 expression and cause a shift in MUFA utilization for complex lipid synthesis and lipid droplet formation. Asah2 deletion modifies hepatocyte and potentially other cell-specific signaling events to mitigate feed-forward regulation of SCD1-Wnt-β catenin signaling. Abbreviations: Asah2, N-acylsphingosine amidohydrolase 2; IgA, immunoglobulin A; MUFA, monounsaturated fatty acid; NASH, nonalcoholic steatohepatitis; SCD1, stearoyl CoA desaturase 1; sIgA, secretory IgA.