Journal
JCI INSIGHT
Volume 6, Issue 7, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.147193
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Funding
- NIH R01 grants [AG043483, DK098656]
- NIH [R01 DK075978]
- US Department of Agriculture Current Research Information System [3092-5-001-059]
- Molecular Pathology and Imaging Core at the Penn Center for Molecular Studies in Digestive and Liver Diseases [DK050306]
- Radioimmunoassay and Biomarkers Core of the Penn Diabetes Research Center [DK19525]
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This study reveals that the loss of mitochondrial deacetylase SIRT3 in hepatocytes impairs liver regeneration and worsens mitochondrial function after partial hepatectomy. While NAD precursor NR promotes liver regeneration, it is shown that neither SIRT3 nor SIRT1 is necessary for NR's enhancing effect. NR improves mitochondrial respiration in regenerating livers and increases oxygen consumption and glucose output in cultured hepatocytes, indicating a direct enhancement of mitochondrial metabolism as the mechanism for improved liver regeneration after NAD supplementation.
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.
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