Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):203-210. doi: 10.1016/j.bbrc.2018.11.008. Epub 2018 Nov 13.
Nonalcoholic fatty liver disease (NAFLD) has increased worldwide in recent years. NAFLD is classified into two types, nonalcoholic fatty liver (NAFL), with few complications, and nonalcoholic steatohepatitis (NASH), which leads to liver cirrhosis or cancer. This study was based on previous reports that N-methylnicotinamide (MNA) can stabilise sirtuin 1 protein, leading to decreased lipid levels in the liver. We hypothesised that fatty liver improvement by MNA would be further enhanced by suppressing its rapid metabolism by aldehyde oxidase in the liver. To test this, hydralazine (HYD), a potent aldehyde oxidase inhibitor, was administered orally to NAFL model rats. Liver triglyceride (TG) levels in the model were nearly unchanged by administration of MNA alone. In contrast, TG levels were marked decreased in NAFL rats treated with a combination of MNA and HYD. In addition, TG levels were decreased even in NAFL rats treated with only HYD. These findings supported our hypothesis that maintaining MNA concentrations in the liver, by suppressing MNA metabolism, would at least partially ameliorate fatty liver.
非酒精性脂肪性肝病（NAFLD）近年来在全球范围内有所增加。NAFLD 分为两种类型，即并发症较少的非酒精性脂肪肝（NAFL）和导致肝硬化或癌症的非酒精性脂肪性肝炎（NASH）。本研究基于先前的报告，即 N-甲基烟酰胺（MNA）可以稳定沉默调节蛋白 1 蛋白，从而降低肝脏中的脂质水平。我们假设通过抑制肝脏中的醛氧化酶来抑制 MNA 的快速代谢，将进一步增强 MNA 对脂肪肝的改善作用。为了验证这一点，我们给 NAFL 模型大鼠口服给予一种强效的醛氧化酶抑制剂肼屈嗪（HYD）。单独给予 MNA 对模型中肝甘油三酯（TG）水平几乎没有影响。相比之下，MNA 和 HYD 联合治疗的 NAFL 大鼠 TG 水平明显降低。此外，仅用 HYD 治疗的 NAFL 大鼠的 TG 水平也降低了。这些发现支持了我们的假设，即通过抑制 MNA 代谢来维持肝脏中 MNA 的浓度，至少可以部分改善脂肪肝。
