## 2 Effects of Nicotinamide Riboside on Several Organs and Systems
### Nicotinamide Riboside and the Digestive System  
In mice subjected to partial hepatectomy, boosting NAD\({}^{+}\) by putting NRS in the drinking water promoted liver regeneration. This was interpreted as increasing DNA biosynthesis at the hepatocyte level and amelioration of hepatic steatosis (HS) [95]. In a high-fat diet (HFD)-fed murine model, NR treatment enhanced hepatic MT function and NAD\({}^{+}\) levels and prevented lipid accumulation in the liver [96]. In vitro, HS was induced in AML12 mouse hepatocytes treated with 250 uM palmitic acid for 48 h. Cell exposure to NR (10 uM and 10 mM) for 24 h did not affect morphology nor viability; instead, it was observed a decrease in TNF-\(\alpha\) and IL-6 proinflammatory markers and an increase in _SIRT1_ gene activity, PGC-1\(\alpha\), transcription factor A, carnitine palmitosyltransferase 1, uncoupling protein 2, mtDNA and MT biogenesis [97].  
Supplementation with NAD\({}^{+}\) precursors (NR, NMN) can prevent liver injury. Proposals to treat non-alcoholic fatty liver disease (NAFLD) NRK1 by targeting HS are based on the discovery that in aged mice or in mice treated with HFD, NRK1 overexpressed by adenovirus-mediated gene transduction regulates lipid metabolism (mainly TG level) and NAD\({}^{+}\) biosynthesis in the liver, insulin sensitivity, and glucose tolerance [98]. In aged mice with a moderate NAFLD-like phenotype, NRS (2.5 g/kg food for three months) significantly reduced the levels of total cholesterol (TC), TG, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and increased the amount of liver NAD\({}^{+}\), diminished inflammatory infiltration, and mitigated HS and liver fibrosis (LF) [99; 100; 101]. In a diet-induced NAFLD model, supplementation with a multi-ingredient mixture of betaine, \(N\)-acetylcysteine, L-carnitine, and NR slowed NAFLD progression and influenced the gut-liver axis through the correction of intestinal microbiota dysbiosis and modulation of short-chain fatty acids (SCFAs) levels in feces [102].  
Daily NR and PT (NRPT, Basis\({}^{\text{TM}}\)) co-administration in 111 adults with NAFLD was assessed in a six-month prospective, randomized, double-blind, PLA-controlled clinical trial. Here, NRPT treatment was well tolerated, and significantly decreased serum levels of ceramide 14:0 (a toxic lipid), ALT, and gamma-glutamyltransferase (GGT) [103].  
In an HFD-induced male C5/BL/6 mice model of LF, NR administration (400 mg/kg/day for 20 weeks) attenuated the development of LF. The body weight, the amount of collagen in the liver, and the activation of hepatic stellate cells (HepSCs) were significantly reduced by NRS, compared to liver inflammation, HS, and ALT levels, which have not been mitigated [104]. In a similar context, NR exhibited a protective effect against LF induced by carbon tetrachloride in mice through an increase in _SIRT1_ gene activity, modulation of Smads signaling pathway acetylation, and suppression of TGF-\(\beta\)-induced HepSCs activation [105].  
NR treatment (400 mg/kg for 16 days) attenuated liver injuries induced by alcohol in C5/BL/6 mice fed a Lieber-DeCarli ethanol liquid diet. The protective effect of NRS involves SIRT1 activation, increasing hepatic NAD\({}^{+}\) levels and PGC-1\(\alpha\) deacetylation, enhancing MT biogenesis/functionality, and decreasing OXS status and ethanol-induced lipid accumulation [106].  
A recent in vitro study in a human hepatic (HepG2) cell line model of citrin deficiency highlighted the potential use of NRS for balancing dysregulated glycolysis and fatty acid \(\beta\)-oxidation [107].  
NRS has even been suggested as being useful to manage the sequelae of infectious diseases. For example, as part of research aimed at new treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, it was highlighted that NRS significantly inhibited the murine hepatitis virus (MHV) replication by increasing the level of NAD\({}^{+}\), activation of the TCA cycle and of MT metabolism [108].