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 (CCl4)‐induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m‐TOR and Akt activity.

SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside

“…The nuclear sirtuin SIRT1 has previously been shown to be required for normal liver regeneration (2,9) (although overexpression may be harmful (11)) and in other settings it has been shown to mediate key effects of NAD precursors, including promoting mitochondrial function and the clearance of fat from hepatocytes (12)(13)(14)(15). Recently, mice lacking another nuclear sirtuin, SIRT6, in hepatocytes were also shown to exhibit delayed regeneration (16). We view SIRT6 as unlikely to be responsible for the effects of NR because it has a high affinity for NAD (Kd of ~ 27 µM (17), well below reported nuclear NAD levels (18)), suggesting that it would be less likely than other sirtuins to respond to modest changes in NAD concentration.…”

“… 11 ), and in other settings it has been shown to mediate key effects of NAD precursors, including promoting mitochondrial function and the clearance of fat from hepatocytes ( 12 – 15 ). Recently, mice lacking another nuclear sirtuin, SIRT6, in hepatocytes were also shown to exhibit delayed regeneration ( 16 ). We view SIRT6 as unlikely to be responsible for the effects of NR because it has a high affinity for NAD ( K D of approximately 27 μM [ref.…”

“…NR enhances mitochondrial respiration in regenerating liver and in primary hepatocytes [10][11][12][13][14][15][16]. …”

Roles of mTOR Signaling in Tissue Regeneration

“…Cyclin D1 and CDK4 form an activation complex to promote liver regeneration via stimulation of G1 to S transition in hepatocytes [185]. Deletion of sirtuin6 (sirt6) , one of the sirtuin family of class III NAD + -dependent histone deacetylase, delays G1 to S phase transition and impairs activation of the Akt/mTOR pathway during liver regeneration [191]. However, SIRT1 overexpression in mice impairs liver regeneration, which can be reversed by the leucine-activated mTORC1 [192].…”

Erratum

“…In the article entitled “Liver‐specific Sirtuin6 ablation impairs liver regeneration after 2/3 partial hepatectomy,” 1 the BrdU staining in Figure 3A of day 7 in Loxp mice was incorrect. Please find the corrected figure below.…”