SIRT3 Is Required for Liver Regeneration but Not for the Beneficial Effect of Nicotinamide Riboside

Authors

Sarmistha Mukherjee
James Mo
Lauren M Paolella
Caroline E Perry
Jade Toth
Mindy M Hugo
Qingwei Chu
Qiang Tong
Karthikeyani Chellappa
Joseph A Baur

Publication Date

4-8-2021

Journal

JCI Insight

DOI

10.1172/jci.insight.147193

PMID

3690226

PMCID

PMC8119200

PubMedCentral® Posted Date

4-8-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Hepatocytes, Liver Regeneration, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mitochondria, Liver, Niacinamide, Oxidation-Reduction, Pyridinium Compounds, Sirtuin 1, Sirtuin 3, Mice, Hepatology, Metabolism, Fatty acid oxidation, Mitochondria, Molecular pathology

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 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.