Medical Service, Veterans Affairs Long Beach Healthcare System, Long Beach 90822, USA.
Am J Physiol Gastrointest Liver Physiol. 2010 Nov;299(5):G1068-77. doi: 10.1152/ajpgi.00249.2010. Epub 2010 Aug 19.
Nonalcoholic fatty liver (NAFL) is a common liver disease, associated with insulin resistance. Betaine has been tested as a treatment for NAFL in animal models and in small clinical trials, with mixed results. The present study aims to determine whether betaine treatment would prevent or treat NAFL in mice and to understand how betaine reverses hepatic insulin resistance. Male mice were fed a moderate high-fat diet (mHF) containing 20% of calories from fat for 7 (mHF) or 8 (mHF8) mo without betaine, with betaine (mHFB), or with betaine for the last 6 wk (mHF8B). Control mice were fed standard chow containing 9% of calories from fat for 7 mo (SF) or 8 mo (SF8). HepG2 cells were made insulin resistant and then studied with or without betaine. mHF mice had higher body weight, fasting glucose, insulin, and triglycerides and greater hepatic fat than SF mice. Betaine reduced fasting glucose, insulin, triglycerides, and hepatic fat. In the mHF8B group, betaine treatment significantly improved insulin resistance and hepatic steatosis. Hepatic betaine content significantly decreased in mHF and increased significantly in mHFB. Betaine treatment reversed the inhibition of hepatic insulin signaling in mHF and in insulin-resistant HepG2 cells, including normalization of insulin receptor substrate 1 (IRS1) phosphorylation and of downstream signaling pathways for gluconeogenesis and glycogen synthesis. Betaine treatment prevents and treats fatty liver in a moderate high-dietary-fat model of NAFL in mice. Betaine also reverses hepatic insulin resistance in part by increasing the activation of IRS1, with resultant improvement in downstream signaling pathways.
非酒精性脂肪性肝病（NAFL）是一种常见的肝脏疾病，与胰岛素抵抗有关。甜菜碱已在动物模型和小型临床试验中被测试为治疗 NAFL 的方法，但结果喜忧参半。本研究旨在确定甜菜碱治疗是否会预防或治疗小鼠的 NAFL，并了解甜菜碱如何逆转肝胰岛素抵抗。雄性小鼠喂食含有 20%脂肪热量的中等高脂肪饮食（mHF）7（mHF）或 8（mHF8）mo 而不添加甜菜碱、添加甜菜碱（mHFB）或在最后 6 wk 添加甜菜碱（mHF8B）。对照小鼠喂食含 9%脂肪热量的标准饲料 7 mo（SF）或 8 mo（SF8）。使 HepG2 细胞产生胰岛素抵抗，然后在有或没有甜菜碱的情况下进行研究。mHF 小鼠的体重、空腹血糖、胰岛素和甘油三酯高于 SF 小鼠，肝脂肪含量也更高。甜菜碱降低了空腹血糖、胰岛素、甘油三酯和肝脂肪。在 mHF8B 组中，甜菜碱治疗显著改善了胰岛素抵抗和肝脂肪变性。mHF 中的肝甜菜碱含量显著降低，mHFB 中的肝甜菜碱含量显著增加。甜菜碱治疗逆转了 mHF 中的肝胰岛素信号抑制以及胰岛素抵抗的 HepG2 细胞中的抑制，包括胰岛素受体底物 1（IRS1）磷酸化和糖异生和糖原合成的下游信号通路的正常化。甜菜碱治疗可预防和治疗小鼠中度高脂肪饮食诱导的 NAFL 模型中的脂肪肝。甜菜碱还通过增加 IRS1 的激活部分逆转肝胰岛素抵抗，从而改善下游信号通路。
