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

Authors: MUKHERJEE, SARMISTHA - University Of Pennsylvania; MO, JAMES - University Of Pennsylvania; PAOLELLA, LAUREN - University Of Pennsylvania; PERRY, CAROLINE - University Of Pennsylvania; TOTH, JADE - University Of Pennsylvania; HUGO, MINDY - University Of Pennsylvania; CHU, QINGWEI - University Of Pennsylvania; TONG, QIAN - Children'S Nutrition Research Center (CNRC); CHELLAPPA, KARTHIKEYANI - University Of Pennsylvania; BAUR, JOSEPH - University Of Pennsylvania

Submitted to: JCI Insight
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/2/2021
Publication Date: 4/8/2021
Citation: Mukherjee, S., Mo, J., Paolella, L.M., Perry, C.E., Toth, J., Hugo, M.M., Chu, Q., Tong, Q., Chellappa, K., Baur, J.A. 2021. SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside. Journal of Clinical Immunology Insights (JCI Insights). 6(7):E147193. https://doi.org/10.1172/jci.insight.147193.
DOI: https://doi.org/10.1172/jci.insight.147193

Interpretive Summary: Liver regeneration is critical to survival after traumatic injuries, toxin damage, or liver surgery. In this study, we show that liver-specific loss of the mitochondrial enzyme SIRT3 drastically impairs liver regeneration after surgical removal of portion of liver. SIRT3 and its family members require nicotinamide adenine dinucleotide (NAD) molecule as a co-factor. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. Our results support a direct enhancement of metabolism as the mechanism mediating improved liver regeneration after NAD supplementation, independent of SIRT1 or SIRT3. Therefore, we provide the first evidence for an essential role of SIRT3 and the beneficial effects of NR during liver regeneration.

Technical Abstract: Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. NR improves mitochondrial respiration in regenerating WT or mutant livers and rapidly increases oxygen consumption and glucose output in cultured hepatocytes. Our data support a direct enhancement of mitochondrial redox metabolism as the mechanism mediating improved liver regeneration after NAD supplementation and exclude signaling via SIRT1 and SIRT3. Therefore, we provide the first evidence to our knowledge for an essential role for a mitochondrial sirtuin during liver regeneration and insight into the beneficial effects of NR.