Role of L-Tryptophan on NAFLD and NASH

L-色氨酸对 NAFLD 和 NASH 的作用

基本信息

批准号：
23790787
负责人：
OSAWA Yosuke
金额：
$ 2.66万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790787/
关键词：
脂肪肝脂肪肝炎トリプトファンセロトニンオートファジー mTOR

项目摘要

Nonalcoholic fatty liver disease is one of the most common liver diseases. L-Tryptophan and its metabolite serotonin are involved in hepatic lipid metabolism and inflammation. However, it is unclear whether L-tryptophan promotes hepatic steatosis. To explore this issue, we examined the role of L-tryptophan in mouse hepatic steatosis by using a high -fat and high-fructose diet (HFHFD) model. L-Tryptophan treatment in combination with a HFHFD exacerbated hepatic steatosis, expression of HNE-modified proteins, hydroxyproline content, and serum ALT levels, whereas L-tryptophan alone did not result in these effects. We also found that L-Tryptophan treatment increasesserum serotonin levels. The introduction of adenoviral aromatic amino acid decarboxylase (AADC), which stimulates the serotonin synthesis from L-tryptophan, aggravated hepatic steatosis induced by the HFHFD. The fatty acid-induced accumulation of lipid was further increased by serotonin treatmen t in cultured hepatocytes. These results suggest that L-tryptophan increases the sensitivity to hepatic steatosis through serotonin production. Furthermore, L-tryptophan treatment, adenoviral AADC introduction, and serotonin treatment induced phosphorylation of the mammalian target of rapamycin (mTOR) and a potent mTOR inhibitor rapamycin attenuated hepatocyte lipid accumulation induced by fatty acid with serotonin. These results suggest the importance of mTOR activation for the exacerbation of hepatic steatosis. In conclusion, L-tryptophan exacerbates hepatic steatosis induced by HFHFD through serotonin-mediated activation of mTOR.

非酒精性脂肪肝是最常见的肝病之一。 L-色氨酸及其代谢物血清素参与肝脏脂质代谢和炎症。然而，尚不清楚L-色氨酸是否促进肝脂肪变性。为了探讨这个问题，我们通过使用高脂肪和高果糖饮食（HFHFD）模型研究了 L-色氨酸在小鼠肝脏脂肪变性中的作用。 L-色氨酸与 HFHFD 联合治疗会加剧肝脏脂肪变性、HNE 修饰蛋白的表达、羟脯氨酸含量和血清 ALT 水平，而单独使用 L-色氨酸不会产生这些影响。我们还发现 L-色氨酸治疗会增加血清血清素水平。腺病毒芳香氨基酸脱羧酶（AADC）的引入，刺激L-色氨酸合成血清素，加剧了HFHFD引起的肝脂肪变性。在培养的肝细胞中，血清素处理进一步增加了脂肪酸诱导的脂质积累。这些结果表明，L-色氨酸通过产生血清素来增加对肝脂肪变性的敏感性。此外，L-色氨酸治疗、腺病毒AADC引入和5-羟色胺治疗诱导了哺乳动物雷帕霉素靶点（mTOR）的磷酸化，并且有效的mTOR抑制剂雷帕霉素减弱了脂肪酸与5-羟色胺诱导的肝细胞脂质积累。这些结果表明 mTOR 激活对于肝脂肪变性恶化的重要性。总之，L-色氨酸通过血清素介导的 mTOR 激活加剧了 HFHFD 诱导的肝脏脂肪变性。