Liver-specific Sirtuin6 ablation impairs liver regeneration after 2/3 partial hepatectomy.

Abstract

Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue-specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver-specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle-related proteins and the immuno staining of Ki-67 and 5-bromo-2-deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m-TOR and Akt activity, which is an important pro-proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl)-induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m-TOR and Akt activity.