NAD+ & Liver Disease
Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor and substrate for many cellular processes. This includes DNA damage repair, energy production and metabolism, intracellular calcium signaling, epigenetically modulated gene expression, and immunological functions. NAD+ levels decrease with age and this decline has been associated with the development of metabolic concerns, such as non-alcoholic fatty liver disease (NAFLD). If left unaddressed, NAFLD can progress to hepatic steatosis, hepatitis, liver cirrhosis, and ultimately, liver dysfunction. Individuals with NAFLD are also at increased risk for hepatocellular carcinoma relative to controls. Pre-clinical studies suggest that low NAD+ levels, such as in the case of inhibition of de novo NAD+ synthesis, may lead to DNA damage, which increases the risk for hepatocellular carcinoma.
The liver is the primary site of de novo biosynthesis of NAD+ from tryptophan, but intracellular NAD+ levels are largely maintained by the salvage pathway. Whether created via de novo synthesis, the salvage pathway, or the Preiss-Handler pathway, our bodies’ NAD+ stores decrease significantly over time. This age-related decline in NAD+ levels may lead to the liver becoming more susceptible to NAFLD and its complications. Replenishing the NAD+ stores by dietary and other means has been shown to mitigate these effects. Research has not been able to demonstrate a significant elevation in plasma or tissue levels of NAD+ with oral supplementation of NAD+ or NADH. This may be the result of inefficient metabolism of NAD+ through the gut, which in turn results in poor bioavailability. It may also be due to NADH not being oxidized to NAD+ in the body, not being efficiently absorbed in the gastrointestinal tract, and/or being converted to another product prior to being
Although the research is still in its infancy, researchers have been able to demonstrate an elevation in plasma NAD+ levels with oral supplementation using some NAD+ precursors, such as nicotinamide riboside (NR). For example, although human randomized, controlled trials evaluating either NAD+ or its precursors in the treatment of liver disease are limited, pre-clinical studies demonstrate that NR may protect against ethanol-induced liver injury by replenishing NAD+11 , may attenuate the development of liver fibrosis, may protect against aging-induced NAFLD, and may promote liver regeneration. While research regarding oral supplementation using NAD+ precursors appears promising, intravenous infusions of NAD+ are currently the only recognized, effective means of increasing systemic NAD+ levels.
In a controlled trial that measured changes in urine and plasma levels of NAD+ and its metabolites during and after a six-hour 3 μmol/min NAD+ intravenous infusion, no change was noted in plasma NAD+ or its metabolites until after two hours, demonstrating that NAD+ is rapidly and completely removed from the plasma for at least the first two hours when infused at an infusion rate of 3 μmol/min. At the six-hour mark, however, the continuous infusion resulted in a 398% increase in plasma NAD+ levels relative to baseline. NAD+ levels remained elevated at the 8-hour mark in the NAD+ group, but not in the saline-treated control group. The results of this study suggest that intravenous administration of NAD+ sufficiently raises plasma NAD+ levels and may be a highly efficacious means of preventing or addressing conditions associated with declines in NAD+, such as fatty liver disease and its complications. No clinically significant adverse effects were noted during the six hour infusion of NAD+ or saline placebo.
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