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Is there a connection between vitamin B3 and liver health? Research suggests that there is. We are seeing studies suggesting that dietary intake of vitamin B3 may play a role in helping with the risk for metabolic dysfunction-associated steatotic liver disease (MASLD), as well as overall mortality among people with this condition. A number of possible mechanisms have been identified supporting this association.
One of the first studies pointing to a risk reduction in liver disease was a cross-sectional study published in the Journal of Clinical Biochemistry and Nutrition, which included data from over 10,500 adults participating in the National Health and Nutrition Examination Survey (NHANES), over 6,000 of whom had a diagnosis of non-alcoholic fatty liver disease (NAFLD). This exploratory analysis of NHANES data was done largely because of niacin’s positive modulation of blood lipids and limited experimental data suggesting a protective effect. Overall, this study found a negative association between dietary niacin intake and NAFLD, with the highest quartile of intake associated with a 24% reduction in risk compared to the lowest. The largest risk reduction was observed among men, ages 60+, people with overweight and obesity, smoking, drinking, and high blood pressure. This analysis had a number of limitations, such as the methods used to estimate niacin intake, the inability to assign causality in a cross-sectional study, etc.
A similar study was published in JAMA Network Open, this time evaluating the association between overall and cardiovascular mortality and niacin intake among a cohort of people with NAFLD. Data from over 4300 adults, again from NHANES, were included using a US Fatty Liver Index (FLI) of 30 or higher as criteria for NAFLD. In the fully adjusted model (adjusted for multiple factors, including age, sex, race and ethnicity, educational, socioeconomic status, smoking status, BMI, total energy intake, diabetes, etc.), people in the highest tertile of intake (≥26.7 mg/d) had a significant 30% lower overall mortality rate than those in the lowest tertile (≤18.4 mg/d). The fully adjusted cardiovascular mortality rate was 35% lower with greater niacin intake, but it was not significant.
A significant interaction with diabetes was also observed; among those with diabetes, only a non-significant 18% lower all-cause mortality rate in the highest tertile was observed, compared to a significant 42% lower rate among people without diabetes. A significantly and substantially lower all-cause mortality rate (74% lower) in the highest tertile of niacin intake was also observed among people with low vitamin B6 intake (< 1.7 mg) compared to those above this threshold. This study is considered to be the only large-scale, prospective cohort study evaluating these associations.
A number of mechanisms have been suggested to explain the potential benefits suggested by the above cohort studies. One may be that niacin increases cellular NAD+ levels, a line of evidence that continues to unfold. Briefly, though, NAD+ is needed for mitochondrial fatty acid oxidation, and hepatic lipid accumulation as well as a decline in NAD+ with aging may interact to increase susceptibility.
Interestingly, a recent study describes a specific mechanism by which NAD+ may mediate its effects. Published in Metabolism, a comprehensive analysis of microRNA (miRNA) expression profiles from both liver tissues from patients with MASLD and diet-induced obese mice revealed a significant upregulation of miR-93. MicroRNAs are short non-coding RNA sequences that regulate gene expression, thereby regulating a variety of cellular processes. This recent study determined that Sirtuin 1 (SIRT1) was the direct target of miR-93, with genetic knockout of miR-93 leading to an increase in the expression of SIRT1. SIRT1 plays an important role in regulating hepatic lipid homeostasis, especially in response to nutrient availability. Knockout of miR-93 also upregulated the expression of genes involved in fatty acid oxidation and downregulated those involved in cholesterol biosynthesis. Niacin was also shown to downregulate miR-93 and ameliorate hepatic stenosis by increasing SIRT1 activity in the experimental model.
This was not the first time niacin has been linked to an increased expression of SIRT1. For example, an in vitro study using human aortic endothelial cells (HAEC) found that niacin increased NAD+ levels and increased nitric oxide production, with this improvement in endothelial function mediated by an NAD+ increase in Sirt1 (the protein product of SIRT1). Additionally, nicotinamide (another form of vitamin B3) was shown to provide protection against hepatotoxicity via SIRT1-dependent mechanisms in a model of NAFLD.
Vitamin B3 may also act via other (potentially overlapping) mechanisms relevant to fatty liver disease, such as reducing LDL cholesterol, triglycerides, and lipoprotein (a) levels. Niacin is also an activator of GPR109A, a G protein-coupled receptor initially thought to be specific only for niacin (but is also activated by 2-hydroxybutyrate). Niacin’s activation of GPR109A has been associated with an inhibition of vascular inflammation and improved endothelial function, which is independent of changes in plasma lipids. In experimental models, niacin has also been shown to inhibit hepatic lipogenesis via GPR109A activation, providing another mechanism for possible protection against MASLD/NAFLD. Certainly, well-designed randomized trials would help to determine the clinical benefits of niacin for both helping prevent MAFLD development and mitigating its harm.
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