NAD+ and NAFLD – Caution, Causality, and Careful Optimism

Posted on 18.05.2021

Are B3 vitamins such as nicotinamide riboside the solution for the ever-growing number of people developing liver fibrosis? Many scientists think so, not least because experiments on mice have shown excellent results. But there are bumps in the road: B3 has turned out to have more limited effects on overweight people than on mice.

A team from the Novo Nordisk Foundation Center for Basic Metabolic Research are now trying to find the explanation. They have published their findings in an review article entitled ‘NAD + and NAFLD – Caution, Causality, and Careful Optimism’.

‘More and more people around the world are getting liver fibrosis and fatty liver, and a treatment is badly needed’, says one of the researchers, Morten Dall, a postdoc on a grant from the Danish Diabetes Academy.

He hopes that he and his colleagues can arrive at an understanding of how the vitamin works and how it helps keep the liver healthy.

‘If we can do that, I believe we can also find a correct way of using it as a treatment’, he says, adding: ‘But then it’s also possible that there’s a difference between the role of the vitamin in humans and in mice…’.

Morten Dall, PhD student Anna S. Hassing (who is also DDA-funded) and group leader Jonas T. Treebak have just had their review article published in the Journal of Physiology.  In it, they summarise observations from preclinical and clinical studies looking at how B3 vitamins may affect fatty liver formation and liver fibrosis, and they attempt to explain why the effects of the vitamin have turned out to be more limited in humans.

For example, they say in the overview article that treatment with vitamin B3 leads to weight loss and improved liver function in mice by improving activation of the cell’s mitochondria, reducing damage from reactive oxygen compounds and inhibiting the progression from fatty liver to liver fibrosis. The latter is due to inhibition of the activity of the cells that form scar tissue in the liver when it is damaged. In overweight humans, vitamin B3 treatment led to a small reduction in the fat content of the liver, but did not affect insulin sensitivity in the liver and did not lead to weight loss.

Morten Dall’s future research plans involve investigating more closely:
– Which patient groups could benefit from the vitamin;
– How liver cells convert the vitamin and what part the vitamin plays in maintaining normal liver function;
– Whether patients with liver fibrosis and fatty liver are deficient in vitamin B3 – ‘We assume so, but we don’t know’, says Morten Dall.

Are liver cells grown in Petri dishes different to those developed in mice?
Right now, Morten Dall has a very exciting project on the go: he is investigating whether liver cells grown in Petri dishes are different to those developed in mice. ‘We can see that a lot changes when we put cells in culture, and we believe this will be of wide interest: a great deal of health research is based on results obtained by cultivation of cells, so, by understanding these changes, we can get a better understanding of the limitations that also go with using cell models.’

B3 vitamins are converted into the co-factor NAD+ (nicotinamide adenine dinucleotide), an important factor in metabolism. NAD+ is used in the cell to produce energy from substrates such as sugar.NAD+ is also used as a substrate by enzymes known as sirtuins, which regulate many metabolic processes such as fatty acid oxidation, adaptation to fasting and mitochondrial function.NAD+ also plays a part in protecting against harmful oxygen compounds (so-called ROS compounds), as it can be converted into the substance NADPH (reduced nicotinamide adenine dinucleotide phosphate), which is an important component of antioxidant defenses.B3 vitamins such as nicotinamide riboside and nicotinamide mononucleotide are sold as dietary supplements, and supplementation with these vitamins has been shown to protect against metabolic disease in mice. It is currently being investigated whether B3 vitamins are usable in a clinical setting.

NAD+ and NAFLD – Caution, Causality, and Careful Optimism.
Dall M, Hassing AS, Treebak JT.
J Physiol. 2021 May 1. doi: 10.1113/JP280908. Online ahead of print.
PMID: 33932956
Published: 1 May 2021

Morten Dall, MSc, PhD
Novo Nordisk Foundation Center for Basic Metabolic Research
+45 35 33 70 88

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