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Niacin, NAFLD & Mortality

iStock-493474022 copy-1Results of a cohort study using NHANES (National Health and Nutrition Examination Survey, 2003-2018) data were recently published in JAMA Network Open, examining the relationship between dietary intake of niacin and both overall and cardiovascular mortality among people with NAFLD (nonalcoholic fatty liver disease). This was a large-scale prospective cohort, including over 4,300 individuals with NAFLD (mean age 52.5) and a median follow-up of 8.8 years, the first to examine this potential association. Niacin intake was estimated by two 24-hour dietary recall interviews, both performed approximately within 1 week of each other, using a standardized and validated assessment method (Automated Multiple-Pass Method). NAFLD was defined by the U.S. Fatty Liver Index (FLI), a calculated value based on multiple variables, including γ-glutamyltransferase, waist circumference, glucose, and insulin.

In a fully adjusted model (including many variables, such as age, sex, race and ethnicity, use of supplements, educational levels, family income to poverty ratio, lipids, diabetes, etc.) a higher intake of niacin was significantly associated with a lower risk for all-cause mortality among people with NAFLD, with an apparent dose-dependent effect. Specifically, the highest tertile of niacin intake (≥26.7 mg/day) compared to the lowest (≤18.4) was associated with a 53% lower all-cause mortality risk (crude), or a 30% lower fully adjusted mortality risk. Although the highest tertile was also crudely associated with a 58% lower mortality from cardiovascular disease specifically, the adjusted models did not find a significant association between niacin intake and cardiovascular disease mortality.

Additionally, a more detailed analysis found that individuals who had diabetes had an 18% lower all-cause mortality risk with higher niacin intake; however, this association was not significant. In contrast, people without diabetes had a significant 42% lower all-cause mortality risk with higher intake. An interaction with vitamin B6 was also observed, with a greater apparent benefit from a higher niacin intake; people with a low intake of B6 (<1.7mg per day) in the highest tertile of dietary niacin had a significant 74% lower all-cause mortality risk than those in the lowest tertile of niacin. No significant association with dietary niacin intake was found for individuals with a B6 intake of 1.7mg or more per day, or for any other B vitamins. This association is likely explained by the requirement for B6 in the conversion of tryptophan to niacin.

Although this was not a randomized trial and cannot demonstrate causality, the robustness of the findings and the magnitude of the all-cause mortality reduction with higher niacin intake are substantial, warranting consideration of possible mechanisms and related research. A previously published small and uncontrolled study found that extended-release niacin significantly reduced triglycerides, liver fat, and visceral fat among study participants with either NAFLD or other metabolic risk factors, particularly hypertriglyceridemia. This study genotyped its participants for hepatic diacylglycerol acyltransferase-2 (DGAT2), the gene coding for the enzyme that catalyzes the last step of triglyceride biosynthesis. An interaction with 2 polymorphisms in this gene with niacin was observed (a greater niacin-induced reduction in hepatic fat was observed with the wild-type alleles), suggesting that niacin may partly act via inhibition of this enzyme, also indicated by in vitro data.

More recent in vitro evidence suggests niacin may have additional mechanisms of action relevant to cardiometabolic health. Using cultures of human aortic endothelial cells (HAEC), niacin was shown to increase cellular levels of NAD+, a coenzyme needed for hundreds of cellular reactions. It’s worth noting that an age-associated decline of NAD+ has been speculated to play a role in metabolic and age-associated disorders. This in vitro study found that not only did niacin increase NAD+ levels, but this increase led to an upregulation of SIRT1 activity and a resulting increase in the endothelial production of nitric oxide. Should this be confirmed in additional studies, it may prove to be a very important biological role for niacin. Similar to NAD+, SIRT1 is involved in many cellular functions, including those related to energy metabolism, and is considered a potential target to improve vascular aging.

In addition to vascular aging, if niacin is able to increase the expression of SIRT1, this may directly improve NAFLD as well. SIRT1 regulates adipocyte accumulation and lipid metabolism and increases mitochondrial biogenesis and fatty acid oxidation. It also increases the expression of liver X receptors (LXRs), thereby increasing the packaging of cholesterol into HDL as well as the metabolism of cholesterol into bile acids. Many natural products, including resveratrol, EGCG, and other polyphenols, have been proposed to improve NAFLD largely via SIRT1 upregulation.

One last pathway also deserves mention; variation in PNPLA3 has been shown to be the strongest genetic predictor of NAFLD and is associated with the risk of progression to fibrosis and cirrhosis of the liver, as well as an 18-fold increase in liver-associated mortality. Experimental models indicate it is associated with increased triglyceride synthesis and response to high carbohydrate diets. Serum levels of niacin, independent of dietary intake, were recently shown to be associated with PNPLA3, and hepatic production of NAD+ was shown to be impaired among patients with this genetic predisposition. Overall, these studies suggest that niacin may play an important role in NAFLD development and progression, and both genetic and nutritional analyses may help predict who would benefit the most from niacin as an intervention.

Related Biotics Research Products:

Niacin 100 

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