背景:肥胖是一种进行性代谢疾病,始于脂质代谢紊乱。芳香族氨基酸(AAAs),包括色氨酸,苯丙氨酸,和酪氨酸,具有多种生物活性作为营养素。然而,AAAs影响脂质代谢的潜在机制尚不清楚。
目的:本研究旨在探讨AAA在脂质代谢紊乱发病中的可能作用和潜在分子机制。
方法:我们将AAA混合物添加到小鼠的高脂肪饮食(HFD)中。记录葡萄糖耐量试验。测定肝胆汁酸(BA)合酶的蛋白表达和BA代谢相关基因的mRNA表达。还在小鼠中测定了肝BA谱和肠道微生物。
结果:结果表明,AAA显着增加了体重和白色脂肪组织,加重肝损伤,糖耐量受损和肠道完整性,并通过抑制肠道法尼醇X受体(FXR)显着增加肝脏BA合成。此外,AAA增加了肝脏中总BA的含量并改变了肝脏BA谱,石胆酸水平升高,糖脱氧胆酸,和甘草脱氧胆酸。AAA显着增加了参与BA合成的蛋白质(胆固醇7α-羟化酶和氧固醇7α-羟化酶)的水平,并抑制了肠道FXR。肠道微生物组成也发生了变化,减少一些有益细菌的丰度,如细小杆菌属和乳酸杆菌。
结论:在HFD条件下,AAAs刺激BA在经典和替代途径中的合成,导致肝脏损伤和脂肪沉积的加重。过量摄入AAA会破坏BA代谢,并有助于脂质代谢紊乱的发展,提示AAA可能是脂质代谢紊乱的病原体。
Obesity is a progressive metabolic disease that begins with lipid metabolism disorders. Aromatic amino acids (AAAs), including tryptophan, phenylalanine, and tyrosine, have diverse biological activities as nutrients. However, the underlying mechanisms by which AAAs affect lipid metabolism are unclear.
This study was designed to investigate the possible roles and underlying molecular mechanisms of AAA in the pathogenesis of lipid metabolism disorders.
We added an AAA mixture to the high-fat diet (HFD) of mice. Glucose tolerance test was recorded. Protein expression of hepatic bile acid (BA) synthase and mRNA expression of BA metabolism-related genes were determined. Hepatic BA profiles and gut microbial were also determined in mice.
The results showed that AAA significantly increased body weight and white adipose tissue, aggravated liver injury, impaired glucose tolerance and intestinal integrity, and significantly increased hepatic BA synthesis by inhibiting intestinal farnesoid X receptor (FXR). Moreover, AAA increased the content of total BA in the liver and altered the hepatic BA profile, with elevated levels of lithocholic acid, glycochenodeoxycholic acid, and glycoursodeoxycholic acid. AAA markedly increased the levels of proteins involved in BA synthesis (cholesterol 7α-hydroxylase and oxysterol 7α-hydroxylase) and inhibited the intestinal FXR. Gut microbial composition also changed, reducing the abundance of some beneficial bacteria, such as Parvibacter and Lactobacillus.
Under HFD conditions, AAAs stimulate BA synthesis in both the classical and alternative pathways, leading to aggravation of liver injury and fat deposition. Excessive intake of AAA disrupts BA metabolism and contributes to the development of lipid metabolism disorders, suggesting that AAA may be a causative agent of lipid metabolism disorders.