Alleviation of fatty liver in a rat model by enhancing N1-methylnicotinamide bioavailability through aldehyde oxidase inhibition

Reduction of fatty liver in rats by nicotinamide via the regeneration of the methionine cycle and the inhibition of aldehyde oxidase

“…The SAM dose was set to 15 mg/kg in this study because a previous study reported improvement of injured blood vessels and anti-inflammatory effect after administering 15 mg/kg SAM for 3 weeks in rats with type 2 diabetes (Lim et al, 2011). Because treatment with 50 mg/kg HYD prevented orotic acid/sucrose-induced fatty liver in rats in a previous study (Takeuchi et al, 2018), the HYD dose was set at 50 mg/kg in this study. Body weight and food consumption were measured once a week.…”

“…The lipid droplets were significantly reduced from the fatty liver as a consequence of enhancing the metabolic reaction (Goto et al, 1998a(Goto et al, , 1998bTakeuchi et al, 2015). Furthermore, we have reported that the combination treatment of the niacin metabolite N 1 -methylnicotinamide (MNA) and the aldehyde oxidase (AO) inhibitor hydralazine (HYD) improved fatty liver in the same NAFL model rats (Takeuchi et al, 2018). MNA has been reported to stabilize sirtuin 1 (SIRT1), which is a protein responsible for fatty acid β-oxidation in the liver, thus reducing hepatic lipid levels (Hong et al, 2015).…”

“…MNA is easily metabolized by AO in the liver, and its oxidation products, namely, N 1 -methyl-2-pyridone-5-carboxamide (2-PY) and N 1 -methyl-4-pyridone-3-carboxamide (4-PY), are immediately excreted into urine (Felsted and Chaykin, 1967;Leifer et al, 1951;Shibata, 1989). Considering that HYD is known as a typical potent AO inhibitor (Obach et al, 2004), it was considered that the rapid metabolism of MNA by AO in the liver was strongly suppressed; as a result, the MNA concentration in the liver was maintained (Takeuchi et al, 2018).…”

NicotinamideN-Methyltransferase: Genomic Connection to Disease

“…13,57 This divergence of results still continues. Some authors report a beneficial effect of NAM/NNMT/MeNAM axis in protecting against a high-fat diet, 58 whereas other authors find the reverse. 59 The conclusion of Trammell and Brenner was that the cell type examined was crucial to the result obtained, but in their deliberations only liver and white fat cells were considered.…”

“…17 Nevertheless, in a rat model, enhancing the bioavailability of MeNAM has been said to alleviate fatty livers. 18 In brain, MeNAM has been claimed to mitigate diabetes-associated brain disorders. 19 In addition to the roles of the enzyme and its methylation product, the NNMT gene (NNMT) itself has been associated with various illnesses, which poses further questions regarding the role of the gene and its relationship to its transcription products and the NNMT enzyme.…”