Consistent with the key role for plasma membrane sn-1,2-DAG-induced PKCε activation in causing hepatic insulin resistance in the aged L-Mttp−/− mice, we show that liver-targeted mitochondrial uncoupling with CRMP reverses hepatic steatosis, plasma membrane sn-1,2-DAG accumulation, hepatic PKCε activation, and hepatic insulin resistance in these mice. Here, SLC38A3 is linked to fatty liver disease.