ABSTRACT
Sirtuins are NAD+-dependent deacylases that are becoming recognized as important regulators of metabolism in the liver. SIRT1 controls metabolism globally through its actions in the nucleus while SIRT3 deacetylates and regulates numerous key proteins involved in mitochondrial energy metabolism. This chapter aggregates recent literature on the lesser studied sirtuins (SIRT2, SIRT4, SIRT5, SIRT6, and SIRT7) and their emerging roles in governing hepatic metabolism. SIRT2, SIRT4, and SIRT5 are nonnuclear sirtuins whose target proteins are just beginning to be elucidated. SIRT2, stimulated by nutrient deprivation, positively regulates gluconeogenesis and suppresses lipogenesis. SIRT6 appears to work in opposition to SIRT2,
Abstract .................................................................................................................. 451 Introduction ............................................................................................................ 452 SIRT2 ..................................................................................................................... 452
SIRT2 and Glucose Homeostasis ...................................................................... 453 Other Glucose-Dependent Interactions of SIRT2 with Target Proteins ............ 455
SIRT4 ..................................................................................................................... 457 SIRT5 ..................................................................................................................... 458
SIRT5 in the Cytosol ......................................................................................... 459 SIRT5 in the Mitochondria................................................................................ 459
SIRT6 .....................................................................................................................460 Activation by Fatty Acids ..................................................................................460 SIRT6 and Glucose Metabolism ....................................................................... 461 SIRT6 and Hepatic Lipid Metabolism .............................................................. 462 SIRT6 and Liver Inammation .........................................................................463
SIRT7 .....................................................................................................................463 SIRT7 and Hepatic Lipid Metabolism ..............................................................463 SIRT7 and Hypoxia ...........................................................................................466 SIRT7 as a Tumor Promoter ..............................................................................466
Future Directions ................................................................................................... 467 References .............................................................................................................. 467
suppressing gluconeogenesis and glucose metabolism in general. SIRT4 represses glutamine and fatty acid oxidation, while SIRT5 promotes ketogenesis and the urea cycle. SIRT6 and SIRT7, which are nuclear-localized, suppress ribosomal biogenesis and hypoxia inducible factor-1 α (HIF1α) signaling. Understanding how the seven sirtuin enzymes communicate across multiple cellular compartments to coordinate metabolism is expected to lead to new therapies for hepatic disease.
