RMSSSHMP · Role of the mitochondrial sirtuins, SIRT3 and SIRT5, in hepatic metabolism and pathology

The function of the three mitochondrial sirtuins SIRT3, 4, and 5 is poorly understood at present. As a limited number of studies have focused on SIRT3, its exact function and regulation in mammalian physiology need still to be elucidated. Likewise, beyond its recently discovered role in the regulation of carbamoyl phosphate synthase 1 (CPS1), nothing is known about the function of SIRT5, one of the other mitochondrial deacetylases from the sirtuin family. The present research project proposes to elucidate the function of SIRT3 and SIRT5 in the liver, a tissue in which both sirtuins are highly expressed. To accomplish this we will achieve the following specific aims: first, generating mice that lack SIRT3, SIRT5, and both SIRT3 and 5 specifically in hepatocytes. Second, evaluating how altering SIRT3 and/or SIRT5 expression levels specifically in liver can affect the hepatic and organismal response to metabolic stresses such as diets rich in carbohydrates and fat, in proteins, or in ethanol, whose metabolism takes place mostly in the mitochondria and, for the most part, in liver cells. Finally, we want to study whether SIRT3 and SIRT5 are involved in liver tumor development: exposure to different tumorigenic stimuli as alcohol-rich diets or certain mutagenic treatments leads to a change in SIRT3 and SIRT5 activity and cellular localization; all this points towards a possible function of these proteins in liver tumor development, an aspect we want to study in this project.We expect that our research will elucidate the basic function of hepatic SIRT3 and SIRT5 in metabolism and cancer. The outcome of our work will not only be useful from a fundamental scientific point of view, but it will also pave the way to new therapies that target SIRT3 and/or SIRT5 or the signaling pathways controlled by them in metabolic disease and hepatocarcinoma, ultimately improving healthspan and healthy aging.