nicotinamide-beta-riboside and Non-alcoholic-Fatty-Liver-Disease

The prevalence of NAFLD is increasing globally and on a path to becoming the most frequent cause of chronic liver disease. Strategies for the prevention and treatment of NAFLD are urgently needed.. A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy of daily NRPT (commercially known as Basis, a combination of nicotinamide riboside and pterostilbene) supplementation in 111 adults with NAFLD. The study consisted of three arms: placebo, recommended daily dose of NRPT (NRPT 1×), and a double dose of NRPT (NRPT 2×). NRPT appeared safe and well tolerated. At the end of the study, no significant change was seen in the primary endpoint of hepatic fat fraction with respect to placebo. However, among prespecified secondary outcomes, a time-dependent decrease in the circulating levels of the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) was observed in the NRPT 1× group, and this decrease was significant with respect to placebo. Furthermore, a significant decrease in the circulating levels of the toxic lipid ceramide 14:0 was also observed in the NRPT 1× group versus placebo, and this decrease was associated with a decrease in ALT in individuals of this group. A dose-dependent effect was not observed with respect to ALT, GGT, or ceramide 14:0 in the NRPT 2× group.. This study demonstrates that NRPT at the recommended dose is safe and may hold promise in lowering markers of hepatic inflammation in patients with NAFLD.

Topics: Adult; Alanine Transaminase; Double-Blind Method; gamma-Glutamyltransferase; Humans; Inflammation; Non-alcoholic Fatty Liver Disease; Prospective Studies

No specific therapy is available for metabolic dysfunction-associated fatty liver disease. We investigated nicotinamide riboside (NR) and dietary restriction (DR) effects in liver lipids, inflammation, histology, intestinal permeability, and gut microbiota in a cafeteria diet (CAFD)-induced obesity model.. Adult male Wistar rats were randomly assigned to standard diet (SD) or CAFD. After 6 wk, they were subdivided into six groups-SD + vehicle (Veh) (distilled water), SD + NR (400 mg/kg), DR + Veh, DR + NR, CAFD + Veh, and CAFD + NR-for 4 wk more until euthanasia.. CAFD increased the hepatic content of lipids, triacylglycerols, and total cholesterol and promoted hepatomegaly, steatosis, steatohepatitis, and liver fibrosis. DR intervention successfully delayed the onset of CAFD-induced liver abnormalities except for steatosis and fibrosis. CAFD suppressed Sirt1 expression in the liver and DR increased Sirt3 expression. CAFD did not affect hepatic inflammatory genes but DR enhanced Il10 expression while decreasing Il1β expression. CAFD reduced Firmicutes and increased Bacteroidetes and Cyanobacteria, with no changes in intestinal permeability. Gut microbiota patterns in animals exposed to DR were similar to those of animals in SD. NR, specifically in CAFD, reduced hepatic triacylglycerols and total cholesterol deposition and collagen fiber accumulation in the liver and limited the colonization of CAFD-induced Cyanobacteria. NR combined with DR decreased the liver's relative weight and Tnfα expression and suppressed Sirt1 and Sirt3 hepatic expression.. This study suggests that NR can be a potential adjuvant to metabolic dysfunction-associated fatty liver disease therapy, encouraging further research in this field.

Topics: Animals; Cholesterol; Diet; Diet, High-Fat; Gastrointestinal Microbiome; Lipids; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Rats; Rats, Wistar; Sirtuin 1; Sirtuin 3; Triglycerides

The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.

Topics: Acetylcysteine; Adult; Animals; Carnitine; Dietary Supplements; Drug Therapy, Combination; Healthy Volunteers; Humans; Male; Metabolomics; Models, Animal; Niacinamide; Non-alcoholic Fatty Liver Disease; Precision Medicine; Pyridinium Compounds; Rats; Serine

Liver fibrosis is part of the non-alcoholic fatty liver disease (NAFLD) spectrum, which currently has no approved pharmacological treatment. In this study, we investigated whether supplementation of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor, can reduce the development of liver fibrosis in a diet-induced mouse model of liver fibrosis.. Male C57BL/6 J mice were fed a low-fat control (LF), a high-fat/high-sucrose/high-cholesterol control (HF) or a HF diet supplemented with NR at 400 mg/kg/day (HF-NR) for 20 weeks. Features of liver fibrosis were assessed by histological and biochemical analyses. Whole-body energy metabolism was also assessed using indirect calorimetry. Primary mouse and human hepatic stellate cells were used to determine the anti-fibrogenic effects of NR in vitro.. NR supplementation significantly reduced body weight of mice only 7 weeks after mice were on the supplementation, but did not attenuate serum alanine aminotransferase levels, liver steatosis, or liver inflammation. However, NR markedly reduced collagen accumulation in the liver. RNA-Seq analysis suggested that the expression of genes involved in NAD+ metabolism is altered in activated hepatic stellate cells (HSCs) compared to quiescent HSCs. NR inhibited the activation of HSCs in primary mouse and human HSCs. Indirect calorimetry showed that NR increased energy expenditure, likely by upregulation of β-oxidation in skeletal muscle and brown adipose tissue.. NR attenuated HSC activation, leading to reduced liver fibrosis in a diet-induced mouse model of liver fibrosis. The data suggest that NR may be developed as a potential preventative for human liver fibrosis.

Topics: Animals; Body Weight; Collagen; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Hepatic Stellate Cells; Humans; Liver; Mice; Mice, Inbred C57BL; Muscle, Skeletal; NAD; Niacinamide; Non-alcoholic Fatty Liver Disease; Pyridinium Compounds