Abstract
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.
Highlights
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
The dyslipidemia that occurs in the metabolic syndrome overloads tissues with lipids, leading to toxic effects such as apoptosis, insulin resistance, maladaptive autophagy, and endoplasmic reticulum (ER) stress [3]; these processes are collectively referred to as “lipotoxicity.” Lipotoxic processes are thought to mediate, at least in part, organ-specific disease processes that ensue in the obese context [4, 5]
Other studies in our laboratory and others indicated that palmitate (C16:0), but not oleate (C18:1), increased expression of sphingosine kinase 1 (SphK1) in skeletal muscle, and that the enzyme was required for expression of proinflammatory genes in primary skeletal muscle cells and in skeletal muscle in mice on a highfat diet [7, 13]
Summary
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. Saturated fat-induced NFB signaling and elevation of TNF␣ 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.—Geng, T., A. Perturbation of lipid biosynthesis occurs, in part, through oversupply of substrates for sphingolipid biosynthetic enzymes, Abbreviations: CD, control diet; ER, endoplasmic reticulum; HPF, high-powered field; HSFD, high saturated fat diet; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ORO, Oil Red O; SphK1, sphingosine kinase 1; S1P, sphingosine-1-phosphate; S1P1(2), sphingosine-1-phosphate receptor 1(2)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
