Departments of Human Genetics and Pediatrics, McGill University, McGill University Health Center (MUHC), Montreal, H4A 3J1, Canada.
Department of Chemistry, Université de Montréal, Montreal, H3T 1J4, Canada.
Mol Nutr Food Res. 2019 Feb;63(3):e1801001. doi: 10.1002/mnfr.201801001. Epub 2018 Nov 23.
Dietary and genetic folate disturbances can lead to nonalcoholic fatty liver disease (NAFLD). A common variant in methylenetetrahydrofolate reductase (MTHFR 677C→T) causes mild MTHFR deficiency with lower 5-methyltetrahydrofolate for methylation reactions. The goal is to determine whether mild murine MTHFR deficiency contributes to NAFLD-related effects.
Wild-type and Mthfr mice, a model for the human variant, are fed control (CD) or high-fat (HFAT) diets for 8 weeks. On both diets, MTHFR deficiency results in decreased S-adenosylmethionine, increased S-adenosylhomocysteine, and decreased betaine with reduced methylation capacity, and changes in expression of several inflammatory or anti-inflammatory mediators (Saa1, Apoa1, and Pon1). On CD, MTHFR deficiency leads to microvesicular steatosis with expression changes in lipid regulators Xbp1s and Cyp7a1. The combination of MTHFR deficiency and HFAT exacerbates changes in inflammatory mediators and introduces additional effects on inflammation (Saa2) and lipid metabolism (Nr1h4, Srebf1c, Ppara, and Crot). These effects are consistent with increased expression of pro-inflammatory HDL precursors and greater lipid accumulation. MTHFR deficiency may enhance liver injury through alterations in methylation capacity, inflammatory response, and lipid metabolism.
Individuals with the MTHFR variant may be at increased risk for liver disease and related complications, particularly when consuming high-fat diets.
饮食和遗传叶酸紊乱可导致非酒精性脂肪性肝病（NAFLD）。亚甲基四氢叶酸还原酶（MTHFR 677C→T）中的常见变异导致轻度 MTHFR 缺乏，甲基化反应的 5-甲基四氢叶酸减少。目的是确定轻度鼠 MTHFR 缺乏是否有助于与 NAFLD 相关的影响。
野生型和 Mthfr 小鼠，人类变异模型，分别用对照（CD）或高脂肪（HFAT）饮食喂养 8 周。在两种饮食中，MTHFR 缺乏导致 S-腺苷甲硫氨酸减少，S-腺苷同型半胱氨酸增加，甜菜碱减少，甲基化能力降低，以及几种炎症或抗炎介质（Saa1、Apoa1 和 Pon1）的表达改变。在 CD 上，MTHFR 缺乏导致微泡性脂肪变性，脂质调节剂 Xbp1s 和 Cyp7a1 的表达发生变化。MTHFR 缺乏和 HFAT 的组合加剧了炎症介质的变化，并引入了对炎症（Saa2）和脂质代谢（Nr1h4、Srebf1c、Ppara 和 Crot）的额外影响。这些影响与促炎 HDL 前体的表达增加和更多的脂质积累一致。MTHFR 缺乏可能通过改变甲基化能力、炎症反应和脂质代谢来增强肝损伤。
携带 MTHFR 变异的个体患肝病和相关并发症的风险可能增加，特别是在食用高脂肪饮食时。
