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.
Highlights
Hepatocytes lost owing to acute injury or over the course of chronic disease are replaced by mitotic division of the remaining mature cells
It has been suggested that NAD biosynthesis and SIRT1 activity are intimately coupled across many tissues [14, 29], and beneficial effects of knocking out other key NAD consumers such as PARP1 and CD38 have been attributed to sparing NAD for SIRT1 or SIRT3 [30,31,32]
In in most of the cases in which a mechanism has been suggested for beneficial effects following NAD supplementation, it involves SIRT1 [27, 28] or in rarer cases, SIRT3 [26, 34]
Summary
Hepatocytes lost owing to acute injury or over the course of chronic disease are replaced by mitotic division of the remaining mature cells. Synthesis of new hepatocytes must be accomplished while the remaining tissue supports multiple indispensable liver functions, including glucose production. There remains no clinically proven therapy to support regeneration in patients at risk for liver failure or following an acute injury or surgical intervention. The early stages of liver regeneration are characterized by a transient decrease in NAD content, which has been attributed to diversion of precursors such as phosphoribosylpyrophosphate (PRPP) to nucleic acid synthesis [3,4,5]. We recently showed that augmenting NAD synthesis, either genetically or by supplementing with the precursor nicotinamide riboside (NR), is sufficient to accelerate liver regeneration in mice [6]. The mechanism by which NAD availability influences the rate of liver regeneration has not yet been elucidated
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