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. This evidence concerns the gene PRKCE and fatty liver disease.