Thus, we found hepatic insulin resistance and PKCε activation was dissociated from hepatic steatosis and total TAG/DAG content in young L-Mttp−/− mice, as the sn-1,2-DAGs were stored in neutral compartments (mostly lipid droplets) in these mice, while hepatic insulin resistance developed in the older L-Mttp−/− mice as sn-1,2-DAGs accumulated in the plasma membrane, leading to PKCε activation and decreased hepatic insulin signaling at the level of the insulin receptor. Here, PRKCE is linked to fatty liver disease.