SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes

• DOI: 10.1194/jlr.m063511
• Publication Date: 2015-10-20T04:30:14Z
• Authors: Tuoyu Geng; Alton Sutter; Michael D. Harland; Brittany A. Law; Jessica S. Ross; David Lewin; Arun Palanisamy; Sarah B. Russo; Kenneth D. Chavin; L.Ashley Cowart
• Keywords: Proinflammatory cytokine; Steatohepatitis; Sphingosine kinase 1; Saturated fatty acid

Steatohepatitis occurs in up to 20% of patients with fatty liver disease and leads its primary outcomes, including fibrosis, cirrhosis, increased risk hepatocellular carcinoma. Mechanisms that mediate this inflammation are major interest. We previously showed overload saturated acids, such as which metabolic syndrome, induced sphingosine kinase 1 (SphK1), an enzyme generates sphingosine-1-phosphate (S1P). While data suggest beneficial roles for S1P some contexts, we hypothesized it may promote hepatic the context obesity. Consistent this, observed 2-fold elevation livers from humans nonalcoholic also mice high fat feeding, recapitulated human disease. Mice exhibited activation NFκB, elevated cytokine production, immune cell infiltration. Importantly, SphK1-null were protected these outcomes. Studies cultured cells demonstrated acid induction SphK1 message, protein, activity, a requirement NFκB signaling mRNA encoding TNFα MCP1. Moreover, fat-induced MCP1 HepG2 was blocked by targeted knockdown receptor 1, supporting role lipid pathway