SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes.
Steatohepatitis occurs in up to 20% of patients with fatty liver disease and leads to its primary disease outcomes, including fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. Mechanisms that mediate this inflammation are of major interest. We previously showed that overload of saturated fatty acids, such as that which occurs with metabolic syndrome, induced sphingosine kinase 1 (SphK1), an enzyme that generates sphingosine-1-phosphate (S1P). While data suggest beneficial roles for S1P in some contexts, we hypothesized that it may promote hepatic inflammation in the context of obesity. Consistent with this, we observed 2-fold elevation of this enzyme in livers from humans with nonalcoholic fatty liver disease and also in mice with high saturated fat feeding, which recapitulated the human disease. Mice exhibited activation of NFκB, elevated cytokine production, and immune cell infiltration. Importantly, SphK1-null mice were protected from these outcomes. Studies in cultured cells demonstrated saturated fatty acid induction of SphK1 message, protein, and activity, and also a requirement of the enzyme for NFκB signaling and increased mRNA encoding TNFα and MCP1. Moreover, saturated fat-induced NFκB signaling and elevation of TNFα and MCP1 mRNA in HepG2 cells was blocked by targeted knockdown of S1P receptor 1, supporting a role for this lipid signaling pathway in inflammation in nonalcoholic fatty liver disease.
Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425.
Tuoyu
T
Geng
Surgery, Medical University of South Carolina, Charleston, SC 29425.
Alton
A
Sutter
Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425.
Michael D
MD
Harland
Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425 Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403.
Brittany A
BA
Law
Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425.
Jessica S
JS
Ross
Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425.
David
D
Lewin
Surgery, Medical University of South Carolina, Charleston, SC 29425.
Arun
A
Palanisamy
Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425.
Sarah B
SB
Russo
Surgery, Medical University of South Carolina, Charleston, SC 29425.
Kenneth D
KD
Chavin
Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425 Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403 cowartl@musc.edu.
L Ashley
LA
Cowart
D000818:Animals; D002460:Cell Line; D005227:Fatty Acids / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099157:Sphingosine Kinase
D005227:Fatty Acids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase
lipid kinases; lipotoxicity; liver, diet and dietary lipids; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; sphingolipids; sphingosine kinase 1; sphingosine-1-phosphate; steatohepatitis