Abstract 13533: Delta-like 4/Notch Signaling Promotes Fatty Liver Disease in Mice
Background: Fatty liver disease is associated with inflammation and cardiometabolic syndrome. We previously demonstrated that the administration of a neutralizing antibody for Delta-like 4 (Dll4), the ligand of Notch signaling, improves key features of cardiometabolic disorders including macrophage activation, atherosclerosis, insulin resistance and hepatic lipid accumulation in mice. The present study has explored the mechanisms through which Dll4/Notch signaling promotes fatty liver.
Methods and Results: We administered Dll4 antibody or control IgG (250 μg, i.p.,twice per week) in high-fat/high-cholesterol fed LDL receptor-deficient mice. Dll4 antibody suppressed prototypical Notch target genes (e.g., Hey1). While body weight and plasma lipid profile did not differ between groups, the livers of mice treated with Dll4 antibody for 4 weeks contained fewer lipids than those of control mice. Dll4 blockade reduced macrophage accumulation in the liver. Dll4 blockade tended to decrease hepatic expression of interleukin-1β (IL-1β), tumor necrosis factor-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1), markers of pro-inflammatory M1 macrophages. Dll4 antibody inhibited expression of diacylglycerol acyltransferase 2, a gene involved in triglyceride synthesis. To further address the role of Dll4 in hepatic inflammation, we performed co-culture experiments of macrophages and hepatocytes. When we exposed the mouse hepatocyte cell line AML12 to conditioned media from Dll4-overexpressing RAW264.7 macrophage cells, mRNA levels of IL-6 and MCP-1 increased.
Conclusion: Dll4/Notch signaling induces hepatocyte inflammation, offering a new therapeutic target for fatty liver.
- © 2013 by American Heart Association, Inc.