Lipid-Induced Toxicity Stimulates Hepatocytes to Release Angiogenic Microparticles That Require Vanin-1 for Uptake by Endothelial Cells

Fat-overloaded hepatocytes release microparticles that induce angiogenesis and worsening of fatty liver disease. Sending an Angiogenic Message Excess amounts of saturated fatty acids are a potential dietary trigger for the fatty liver disease steatohepatitis, in which the liver develops fat deposits and inflammation. Progression of the disease to more serious forms, which can include scarring and other serious complications, is associated with the formation of new blood vessels, a process called angiogenesis, which requires endothelial cells to migrate and form tubular structures. Povero et al. found that a hepatocyte cell line exposed to excess amounts of saturated fatty acids released membrane-bound microparticles that induced angiogenesis when administered to mice. Microparticles from the blood of mice with diet-induced steatohepatitis originated from the liver and triggered migration and tubular structure formation when applied to an endothelial cell line. The angiogenic effects of microparticles generated by a hepatocyte cell line exposed to saturated fatty acids or of those from mice with diet-induced steatohepatitis involved the uptake of the microparticles by endothelial cells, a process that required Vanin-1, an enzyme located on the surface of the microparticles. Thus, the pathological angiogenesis that can occur in steatohepatitis could be reduced by preventing endothelial cells from internalizing Vanin-1–positive microparticles from hepatocytes. Angiogenesis is a key pathological feature of experimental and human steatohepatitis, a common chronic liver disease that is associated with obesity. We demonstrated that hepatocytes generated a type of membrane-bound vesicle, microparticles, in response to conditions that mimicked the lipid accumulation that occurs in the liver in some forms of steatohepatitis and that these microparticles promoted angiogenesis. When applied to an endothelial cell line, medium conditioned by murine hepatocytes or a human hepatocyte cell line exposed to saturated free fatty acids induced migration and tube formation, two processes required for angiogenesis. Medium from hepatocytes in which caspase 3 was inhibited or medium in which the microparticles were removed by ultracentrifugation lacked proangiogenic activity. Isolated hepatocyte-derived microparticles induced migration and tube formation of an endothelial cell line in vitro and angiogenesis in mice, processes that depended on internalization of microparticles. Microparticle internalization required the interaction of the ectoenzyme Vanin-1 (VNN1), an abundant surface protein on the microparticles, with lipid raft domains of endothelial cells. Large quantities of hepatocyte-derived microparticles were detected in the blood of mice with diet-induced steatohepatitis, and microparticle quantity correlated with disease severity. Genetic ablation of caspase 3 or RNA interference directed against VNN1 protected mice from steatohepatitis-induced pathological angiogenesis in the liver and resulted in a loss of the proangiogenic effects of microparticles. Our data identify hepatocyte-derived microparticles as critical signals that contribute to angiogenesis and liver damage in steatohepatitis and suggest a therapeutic target for this condition.