| Popis: |
The liver is one of the major organs for lipid metabolism. Disruption of lipid homeostasis in the liver may cause the development of many metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). Histone deacetylase sirtuin 6 (SIRT6) regulates multiple biological processes via its deacetylation, deacylation, and mono-ADP-ribosylation activities. The role of SIRT6 in lipid metabolism is not fully understood. In this project, we aim to determine the impact of hepatic SIRT6 on the progression of diet-induced metabolic disorders in wild-type or Ldlr-deficient mice. We fed the control mice and mice lacking or overexpressing hepatic SIRT6 a diet enriched in fats and cholesterol, with or without fructose, to induce metabolic disorders. We investigated the effect of SIRT6 on the development of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), atherosclerosis, and obesity. Our results show that adeno-associated virus serotype 8 (AAV8)-mediated overexpression of human SIRT6 in the liver ameliorates diet-induced NAFLD, atherosclerosis and obesity, whereas loss of hepatocyte SIRT6 has opposite effects. Further studies show that SIRT6 inhibits lipid droplet formation, apoptosis, bile acid synthesis, and intestinal fat and cholesterol absorption. Our data indicate that hepatic SIRT6 may be a promising therapeutic target for the treatment of metabolic disorders. |
