A team from the Department of Physiology and Institute for Diabetes, Obesity and Metabolism of Perelman School of Medicine, University of Pennsylvania investigated whether NAD availability limits regeneration capacity of the liver from surgical resection or injuries caused by trauma or toxins.
In general the liver possesses remarkable capacity to regenerate. It is known that as little as 25% of the original liver mass can regenerate back to its full size providing there is the right amount of nutrients, enzymes etc available. The ability for the liver to regenerate is central to liver homeostasis. Because the liver is the main site of drug detoxification, it is exposed to many chemicals in the body which may potentially induce cell death and injury. Its ability to regenerate prevents its failure.
A liver injury trauma, also known as liver laceration, can for example occur through either a blunt force such as a car accident, or a penetrating knife or gun shot. Drug-induced liver injuries appears to happen regularly as they are responsible for 5% of all hospital admissions and 50% of all acute liver failures. Drug-induced injuries happen for example when taking paracetamol while also consuming alcohol.
In humans so called hepatectomies (partial removal of liver) is performed for the treatment of hepatic neoplasms (cancer), both benign or malignant. The most common malignant neoplasms (cancers) of the liver are metastases which for example arise from colorectal cancer. Hepatectomy is also used to treat gallstones or parasitic cysts of the liver.
It is known that during liver regeneration, the concentration of nicotinamide adenine dinucleotide (NAD) falls. The reserachers wanted to test whether the availability of NAD limits the rate of liver regeneration. In other to do that they supplied nicotinamide riboside (NR) in the drinking water of mice subjected to partial hepatectomy. NR is a well known precursor for NAD and research has shown it also raises NAD+ in humans.
As compared to the control mice the NR supplementation increased DNA synthesis, mitotic index (=the ratio between the number of cells in a population undergoing mitosis (cell division) to the number of cells not undergoing mitosis), and mass restoration in the regenerating livers. The reserachers also noted that NR reduced steatosis that normally accompanies liver regeneration. Steatosis (fatty liver) is an accumulation of fat in the liver which is unwanted.
An interesting experiment by the reserachers was the creation of of mice overexpressing Nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme for NAD synthesis. These Nampt overexpressing mice also exhibited enhanced liver regeneration and reduced steatosis. Mice lacking Nampt in the hepatocytes showed poor regenerative capacity which was completely rescued by administering NR.
With clear results as outcome of the experiements it was easy for the researchers to conclude that NAD availability is limiting during liver regeneration and supplementation with precursors such as NR may be therapeutic in settings of acute liver injury. They also noted that additional investigation into downstream mechanisms and optimal delivery strategies is warranted.
Using FDA specified guidelines we can calculate the Human Equivalent Dose (HED) for the NR diet given to the mice via the drinking water. The drinking water contained 3 mg/ml of NR, with mice drinking about 3ml per day and the weight of a mouse about 30 grams that translates in a dosing value of 500 mg/kg/day. This results into a HED of approx. 41mg/kg which means 2.8g daily NR dosing for a person weighing 70kg. This is a very high dose but because it is here used for a limited period of time and for therapeutic purpose to recover from liver injury this may not be an issue. Having said that repetition of the experiment to find out whether similar results also occur at lower dosing levels would be useful.
Overall this appears to be a succesfull study into the application of nicotinamide riboside in a therapeutic use case and hopefully this will lead to further research in humans resulting in faster and fuller recovery of liver injury.
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