Branched-chain amino acid (BCAA) metabolism is associated with triglyceride (TG) metabolism and the development of cardiovascular disease (CVD). However, the underlying mechanism remains uncertain. This study included 1302 subjects and followed for 4–5 years. A hyperbranched-chain aminoacidemia rat model was induced by high fructose diet (HFTD). The relationship between BCAAs and TG level and its regulatory mechanism was investigated in vitro. As results, as baseline BCAA percentile increased, subjects had higher prevalence and incidence of T2DM, NAFLD, and CVD risk (P < 0.05). In animal model, the accumulation of BCAAs and TG and betatrophin expression were significantly elevated in the HFTD group when comparing with those in the SD group(P < 0.05). Immunofluorescence and Masson's trichrome staining revealed that the area of interstitial fibrosis was significantly increased in the HFTD group compared with control group. Met treatment significantly decreased TG levels and betatrophin expression and reversed myocardial fibrosis (P < 0.05). In vitro, LO2 cells, stimulated with 0.1–5 mM BCAAs, displayed a significant dose-dependent increase in betatrophin expression (P < 0.05). And 5 mM BCAAs stimulation significantly increased the p-mTOR and SREBP-1 expression (P < 0.05). However, this effect could be reversed by using the corresponding inhibitor or siRNAs. In conclusions, BCAAs promote occurrence and development of cardiovascular disease dependent on TG metabolism via activation of the mTOR/SREBP-1/betatrophin pathway. The study provides a new theory for the pathogenesis of CVD caused by amino acid metabolism disorders.

中文翻译：

---

支链氨基酸通过激活mTOR/SREBP-1/betatropin途径促进依赖于甘油三酯代谢的心血管疾病的发生和发展

支链氨基酸（BCAA）代谢与甘油三酯（TG）代谢和心血管疾病（CVD）的发展相关。然而，其根本机制仍不确定。这项研究包括 1302 名受试者，并随访了 4-5 年。采用高果糖饮食（HFTD）诱导高支链氨基酸血症大鼠模型。体外研究BCAA与TG水平的关系及其调控机制。结果，随着基线 BCAA 百分位的增加，受试者 T2DM、NAFLD 和 CVD 风险的患病率和发生率较高（P < 0.05）。动物模型中，与SD组相比，HFTD组BCAAs和TG的积累以及betatropin表达均显着升高（P < 0.05）。免疫荧光和Masson三色染色显示，与对照组相比，HFTD组间质纤维化面积明显增大。 Met 治疗显着降低 TG 水平和 betatropin 表达并逆转心肌纤维化（P < 0.05）。在体外，用 0.1-5 mM BCAA 刺激后，LO2 细胞的 betatropin 表达出现显着的剂量依赖性增加（P < 0.05）。 5 mM BCAA 刺激显着增加 p-mTOR 和 SREBP-1 表达（P < 0.05）。然而，这种效应可以通过使用相应的抑制剂或 siRNA 来逆转。总之，支链氨基酸通过激活 mTOR/SREBP-1/betatropin 通路促进依赖于 TG 代谢的心血管疾病的发生和发展。该研究为氨基酸代谢紊乱引起的CVD发病机制提供了新的理论。