Objective Hepatic steatosis accompanying obesity is a major health concern, since it may initiate non-alcoholic fatty liver disease (NAFLD) and associated complications like cirrhosis or cancer. Intestinal gluconeogenesis (IGN) is a recently described function that contributes to the metabolic benefits of specific macronutrients as protein or soluble fibre, via the initiation of a gut-brain nervous signal triggering brain-dependent regulations of peripheral metabolism. Here, we investigate the effects of IGN on liver metabolism, independently of its induction by the aforementioned macronutrients. Design To study the specific effects of IGN on hepatic metabolism, we used two transgenic mouse lines: one is knocked down for and the other overexpresses glucose-6-phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine. Results We report that mice with a genetic overexpression of IGN are notably protected from the development of hepatic steatosis and the initiation of NAFLD on a hypercaloric diet. The protection relates to a diminution of de novo lipogenesis and lipid import, associated with benefits at the level of inflammation and fibrosis and linked to autonomous nervous system. Conversely, mice with genetic suppression of IGN spontaneously exhibit increased hepatic triglyceride storage associated with activated lipogenesis pathway, in the context of standard starch-enriched diet. The latter is corrected by portal glucose infusion mimicking IGN. Conclusion We conclude that IGN per se has the capacity of preventing hepatic steatosis and its eventual evolution toward NAFLD.

中文翻译：

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肠道糖异生可预防肥胖相关的脂肪肝和非酒精性脂肪肝

目的 伴随肥胖的肝脂肪变性是一个主要的健康问题，因为它可能引发非酒精性脂肪肝 (NAFLD) 和相关并发症，如肝硬化或癌症。肠道糖异生 (IGN) 是最近描述的一种功能，通过启动肠脑神经信号触发外周代谢的脑依赖性调节，有助于特定常量营养素作为蛋白质或可溶性纤维的代谢益处。在这里，我们研究了 IGN 对肝脏代谢的影响，独立于上述宏量营养素的诱导。设计 为了研究 IGN 对肝脏代谢的具体影响，我们使用了两种转基因小鼠品系：一种被敲低，另一种过度表达葡萄糖 6-磷酸酶，这是内源性葡萄糖产生的关键酶，特别是在肠道。结果我们报告说，IGN 基因过表达的小鼠在高热量饮食中显着免受肝脏脂肪变性的发展和 NAFLD 的发生。该保护涉及减少从头脂肪生成和脂质输入，与炎症和纤维化水平的益处相关，并与自主神经系统相关。相反，在标准富含淀粉的饮食的背景下，IGN 基因抑制的小鼠自发地表现出与激活的脂肪生成途径相关的肝脏甘油三酯储存增加。后者通过模拟 IGN 的门静脉输注葡萄糖来纠正。结论 我们得出结论，IGN 本身具有预防肝脂肪变性及其最终演变为 NAFLD 的能力。结果我们报告说，IGN 基因过表达的小鼠在高热量饮食中显着免受肝脏脂肪变性的发展和 NAFLD 的发生。该保护涉及减少从头脂肪生成和脂质输入，与炎症和纤维化水平的益处相关，并与自主神经系统相关。相反，在标准富含淀粉的饮食的背景下，IGN 基因抑制的小鼠自发地表现出与激活的脂肪生成途径相关的肝脏甘油三酯储存增加。后者通过模拟 IGN 的门静脉葡萄糖输注来纠正。结论 我们得出结论，IGN 本身具有预防肝脂肪变性及其最终演变为 NAFLD 的能力。结果我们报告说，IGN 基因过表达的小鼠在高热量饮食中显着免受肝脏脂肪变性的发展和 NAFLD 的发生。该保护涉及减少从头脂肪生成和脂质输入，与炎症和纤维化水平的益处相关，并与自主神经系统相关。相反，在标准富含淀粉的饮食的背景下，IGN 基因抑制的小鼠自发地表现出与激活的脂肪生成途径相关的肝脏甘油三酯储存增加。后者通过模拟 IGN 的门静脉葡萄糖输注来纠正。结论 我们得出结论，IGN 本身具有预防肝脂肪变性及其最终演变为 NAFLD 的能力。