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.

Using Biochemistry to Educate Students on the Causal Link between Social Epigenetics and Health Disparities.

BACKGROUND: While pharmacy education standards require students to recognize social determinants of health (SDOH), there is an opportunity to improve how this is taught in the curriculum. One innovative approach is to educate student pharmacists in a biochemistry course through the integration of topics like epigenetics using SDOH as the framework. INNOVATION: A 50-minute educational activity was used to supplement material on the regulation of gene expression, in which epigenetic changes are driven by SDOH. It provided students with a biochemical basis to explain some health disparities, rather than viewing them exclusively as social obstacles to health. The activity employed a mini-lecture, a short video, as well as both small and large group discussion. A reflective paper was used to assess students' understanding of the topic, and the role of the pharmacist in helping patients prevent diseases caused by epigenetic changes due to social determinants of health. FINDINGS: A post-activity survey showed that the activity increased students' perception of knowledge about SDOH, as well as the effect of epigenetic changes on health outcomes. Furthermore, this activity increased students' awareness about the role that SDOH play in epigenetic changes and challenged students to understand the role that society plays in health outcomes. CONCLUSIONS: The preventable nature of health inequities creates an opportunity to integrate public health into pharmacy education. The integration of epigenetics and SDOH gives the student an opportunity to provide a mechanistic link between social inequities and biochemical processes.