Hepatocellular autotaxin is a major source of systemic lysophosphatidic acid and regulates glucose homeostasis

Autotaxin (ATX) is a secretory lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA) and thereby regulates diverse cellular functions such as migration, survival, proliferation and metabolism. Adipocytes are known as significant source of systemic LPA under physiological conditions. Evidence suggests that LPA regulates glucose levels, but the role of ATX in glucose homeostasis is unknown. Here we investigated the role of hepatocellular ATX in glucose homeostasis using mice with heptocyte-specific Atx knockout (Atxh-/h-) generated by crossing mice with floxed Atx gene and AlbCre mice. The data indicate that the blood levels of LPA in Atxh-/h- mice were reduced by approximately 50% as compared to AlbCre mice. Basal glucose levels were similar in normally fed Atxh-/h- and AlbCre mice, whereas Atxh-/h- mice showed an increased disposal rate of injected glucose from the blood. Atxh-/h- mice showed a stronger increase of the blood glucose concentration in response to glucagon, a higher gluconeogenic capacity, and higher fasting glucose levels. This study provides the first evidence that hepatocellular ATX is the major source of systemic LPA under physiological conditions. It affects glucometabolism by two divergent mechanisms: by inhibiting glucose removal from the circulation and lowering the glycemic effect of glucagon, implying a novel role in hepatic glucose regulation.