Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Department of Veterinary Medical Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Sci Rep. 2018 Apr 3;8(1):5461. doi: 10.1038/s41598-018-23640-8.
We previously reported that a low-protein diet caused animals to develop fatty liver containing a high level of triglycerides (TG), similar to the human nutritional disorder "kwashiorkor". To investigate the underlying mechanisms, we cultured hepatocytes in amino acid-sufficient or deficient medium. Surprisingly, the intracellular TG level was increased by amino acid deficiency without addition of any lipids or hormones, accompanied by enhanced lipid synthesis, indicating that hepatocytes themselves monitored the extracellular amino acid concentrations to induce lipid accumulation in a cell-autonomous manner. We then confirmed that a low-amino acid diet also resulted in the development of fatty liver, and supplementation of the low-amino acid diet with glutamic acid to compensate the loss of nitrogen source did not completely suppress the hepatic TG accumulation. Only a dietary arginine or threonine deficiency was sufficient to induce hepatic TG accumulation. However, supplementation of a low-amino acid diet with arginine or threonine failed to reverse it. In silico analysis succeeded in predicting liver TG level from the serum amino acid profile. Based on these results, we conclude that dietary amino acid composition dynamically affects the serum amino acid profile, which is sensed by hepatocytes and lipid synthesis was activated cell-autonomously, leading to hepatic steatosis.
我们之前曾报道过，低蛋白饮食会导致动物产生富含甘油三酯（TG）的脂肪肝，类似于人类的营养失调“夸希奥科”。为了研究其潜在机制，我们在氨基酸充足或缺乏的培养基中培养肝细胞。令人惊讶的是，氨基酸缺乏会在不添加任何脂质或激素的情况下增加细胞内 TG 水平，同时伴随着脂质合成的增强，表明肝细胞本身会监测细胞外氨基酸浓度，以自主方式诱导脂质积累。然后，我们证实低氨基酸饮食也会导致脂肪肝的发生，并且用谷氨酸补充低氨基酸饮食以补偿氮源的损失并不能完全抑制肝 TG 的积累。只有饮食中精氨酸或苏氨酸缺乏才能诱导肝 TG 积累。然而，用精氨酸或苏氨酸补充低氨基酸饮食并不能逆转这种情况。基于这些结果，我们得出结论，饮食中氨基酸的组成会动态影响血清氨基酸谱，而这种谱会被肝细胞感知，从而自主激活脂质合成，导致肝脂肪变性。
