Nicotinamide Riboside reverses fatty liver disease in mice

Nonalcoholic fatty liver disease (NAFLD) is a term used to describe the accumulation of fat in the liver of people who drink little or no alcohol. It is also the most common cause of chronic liver disease in Western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. At its most severe, nonalcoholic fatty liver disease can progress to liver failure.

Its pathogenesis is complex, the disease is the result of a multi-factorial process in which insulin resistance seems to play a major role in the initial accumulation of fat in the liver, whereas multiple causes of mitochondrial dysfunction and oxidative stress can induce the secondary occurrence of necroinflammatory lesions and fibrosis.

In the report the researchers noted that recent evidence demonstrates that nicotinamide adenine dinucleotide (NAD+) boosting protects organisms from metabolic diseases, induced by genetic factors, diet, or aging. The findings corroborate the role and activation of sirtuins, many of which rely on NAD+ as a cosubstrate, in triggering metabolic improvements. They also noted that the role of NAD+ in the development and protection from NAFLD was still unspecified as well as the influence of NAD+ boosting in mice with preexisting liver hyperlipidemia and aberrant lipid metabolism.

In this study, the researchers demonstrate that a Western diet, including high levels of fat and sucrose may contribute to the development of NAFLD, and that NAD+ boosting by feeding animals with a diet enriched in nicotinamide riboside may prevent or reverse NAFLD by inducing the mitochondrial unfolded protein response (UPRmt) which in turn triggers a mitohormetic response.

This mechanism of sirtuin-dependent mitochondrial changes was recently shown to rely, in part, on induction of UPRmt, triggered by an imbalance in mitochondrial- versus nuclear-encoded mitochondrial proteins. This mitonuclear imbalance activates a retrograde signal that induces a mitohormetic and adaptive nuclear response, ultimately repairing and improving mitochondrial function.

Several animal cohorts e.g. SIRT knockout, were fed either a Western high-fat and high-sucrose diet or normal chow diet (CD) and / or pellets containing vehicle or NR (400-500mg/kg/day) between and 18 weeks.

From the data, the researchers postulated that boosting NAD+ levels increases sirtuin-mediated UPRmt activation and mitochondrial biogenesis, while also reducing UPRer stress response. In agreement, they found nicotinamide riboside attenuated the severe mitochondrial dysfunction, typified by reduced mitochondrial content and function, present in fatty livers of mice fed a long-term high-fat high-sucrose diet. These robust effects of NR on mitochondrial function were reliant on the NAD+-mediated SIRT1 and SIRT3 induction of mitonuclear protein imbalance, triggering the UPRmt. Similar to previous reports linking the beneficial effects of NR to the UPRmt activation of UPRmt in livers of these NR-treated animals maintained optimal mitochondrial function despite a chronic FA overload.

Overall the data shows that boosting of depleted liver NAD+ stores in mouse models of NAFLD, by administration of Nicotinamide Riboside supplements, recovers liver NAD+-dependent SIRT1 and SIRT3 signaling to counteract the development of NAFLD. And that the beneficial effects of NR are largely mediated by the cell-autonomous effect of SIRT1 activation in the liver.

As always for perspective we calculate the Human Equivalent Dose (HED) for the nicotinamide riboside diet given to the mice. The FDA has specified guidelines for this conversion to Human Equivalent Dose (HED). Using this guideline 500 mg/kg dosing in mice translates into a HED of approx. 40mg/kg. Or into approximately 2.2gram daily nicotinamide riboside dose for a person weighing 70kg. Typical supplements on the market have serving sizes of 250mg. It should also be noted that this dose is on the high end wrt to side effects and safety and therefore a therapeutic approach likely to be done under medical supervision.

Leave a Reply