Fatty liver disease affects approximately 30% of adults in the US. The disease is initially manifested as simple steatosis, but can progress into more serious problems like inflammation, fibrosis, cirrhosis, and even liver cancer. Dr. Dong’s laboratory investigates the molecular pathogenesis of the fatty liver disease and aims to identify novel therapeutic targets. Recently, they have discovered sirtuin 6 (SIRT6) and sestrin 1/2/3 genes as key players in the protection against fatty liver disease. SIRT6 is an NAD-dependent deacetylase and deacylase. Hepatic SIRT6 deficiency exacerbates diet-related fatty liver disease in mice. Biochemical and molecular biological analysis revealed a critical role of SIRT6 in the suppression of lipogenesis and fibrogenesis by controlling master regulators in those processes. For the sestrin studies, they have used both animal and cell models to uncover multiple beneficial functions of sestrins in the liver through regulation of several signaling pathways including mTOR, Hedgehog, SMAD3, and JNK. These findings provide useful knowledge basis for future therapeutic development.