The role of the endothelial cell-derived semaphorin3a in non-alcoholic hepatic steatosis, insulin sensitivity and glucose tolerance

Type 2 Diabetes Mellitus (T2DM) is an epidemic metabolic disorder resulting in chronically elevated blood glucose levels and severe secondary complications. It is frequently accompanied with an ectopic accumulation of lipids... [ view full abstract ]

Type 2 Diabetes Mellitus (T2DM) is an epidemic metabolic disorder resulting in chronically elevated blood glucose levels and severe secondary complications. It is frequently accompanied with an ectopic accumulation of lipids in hepatocytes (non-alcoholic hepatosteatosis), a condition promoting insulin resistance and cardiovascular diseases. Here we study the role of the secreted protein Semaphorin3a (SEMA3A) in hepatosteatosis, insulin resistance and glucose homeostasis in mice. We found that Sema3a expression is increased in livers of insulin resistant (high-fat diet-fed) and db/db diabetic mice. Notably, Sema3a is expressed in mouse and human liver sinusoidal endothelial cells (LSECs) and SEMA3a receptors are present in mouse and human hepatocytes, respectively, principally enabling Sema3a signaling in hepatocytes. In line with this, high-fat diet-fed Sema3a heterozygous KO mice displayed decreased liver fat as well as improved insulin sensitivity and glucose tolerance. This could also be observed in mice with an endothelial cell-specific deletion of Sema3a which also displayed lower liver fat, improved insulin sensitivity and glucose tolerance. Our results suggest that SEMA3a negatively regulates insulin sensitivity and that attenuation of the SEMA3a pathway may improve insulin sensitivity and glucose tolerance.